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| United States Patent |
5,719,280
|
|
Martinez
, et al.
|
February 17, 1998
|
Benzocycloalkylazolethione derivatives and processes for preparing the
same
Abstract
The present invention relates to novel benzocycloalkylazolethione compounds
which are dopamine .beta.-hydroxylase inhibitors in which the
benzocycloalkyl portion of the compound is selected from indanyl,
1,2,3,4-tetrahydronaphthalenyl and
6,7,8,9-tetrahydro-5H-benzocycloheptenyl (in which the benzo is optionally
substituted with one to three substituents) and the azolethione portion of
the compound is selected from 2-thioxo-2,3-dihydro-1H-imidazol-3-yl,
5-thioxo-4,5-dihydro-1H-›1,2,4!triazol-4-yl and
5-thioxo-4,5-dihydro-1H-›1,2,4!triazol-1-yl (each optionally substituted
with one to three substituents); and the prodrugs, pharmaceutically
acceptable salts, individual isomers and mixtures of isomers and the
methods of using and preparing such benzocycloalkylazolethione compounds.
| Inventors:
|
Martinez; Gregory Ricardo (Mountain View, CA);
Gooding; Owen Will (Los Gatos, CA);
Repke; David Bruce (Milpitas, CA);
Teitelbaum; Philip Jay (Boulder Creek, CA);
Walker; Keith Adrian Murray (Los Altos Hills, CA);
Whiting; Roger Lewis (Los Altos, CA)
|
| Assignee:
|
Syntex (U.S.A.) Inc. (Palo Alto, CA)
|
| Appl. No.:
|
833560 |
| Filed:
|
April 7, 1997 |
| Current U.S. Class: |
544/132; 544/139; 544/360; 544/370; 546/210; 548/263.2; 548/263.8; 548/314.7; 548/324.5; 564/428; 564/460; 564/462 |
| Intern'l Class: |
C07D 403/04; C07D 233/60 |
| Field of Search: |
544/132,139,360,370
546/210
548/263.2,263.8,314.7,324.5
564/428,460,462
|
References Cited
U.S. Patent Documents
| 3547942 | Dec., 1970 | Godefroi et al. | 260/309.
|
| 4994103 | Feb., 1991 | De Bruyn et al.
| |
| Foreign Patent Documents |
| 0 207 563 A2 | Jan., 1987 | EP.
| |
| 0371733 | Jun., 1990 | EP.
| |
| 0371730 | Jun., 1990 | EP.
| |
| 0371732 | Jun., 1990 | EP.
| |
Other References
Schubert, et al., 76683u "Synthesis and ring closure reactions of imidazole
4,5-dialdehydes", Chemical Abstracts 75:457 (1971).
De Bruyn et al., 38996g "Preparation of 1H-imidazole-5-carboxylic acid
derivatives as herbicides", Chemical Abstracts 110:546 (1989).
Kruse et al., "Multisubstrate Inhibitors of Dopamine .beta.-Hydroxylase. 1.
Some 1-Phenyl and 1-Phenyl-Bridged Derivatives of Imidazole-2-thione", J.
Med. Chem., 29:2465-2472 (1986).
Kruse et al., "Multisubstrate Inhibitors of Dopamine .beta.-Hydroxylase. 2.
.sup.1 Structure-Activity Relationships at the Phenethylamine Binding
Site", J. Med. Chem. 30:486-494 (1987).
Bjork et al., "Resolved N,N-Dialkylated 2-Amino-8-hydroxytetralins:
Stereoselective Interactions with 5-HT.sub.1A Receptors in the Brain", J.
Med. Chem. 32:779-784 (1989).
Hillver et al., "(S)-5-Fluoro 8-hydroxy-2-(dipropylamino)tetralin: A
Putative 5-HT.sub.1A -Receptor Antagonist", J. Med. Chem. 33:1541-1544
(1990).
Wyrick et al., "Synthesis and Pharmacological Evaluation of
1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as Ligands for a Novel
Receptor with .sigma.-like Neuromodulatory Activity" J. Med. Chem.
36:2542-2551 (1993).
Kawasaki et al., "Asymmetric Reduction of Prochiral Cyclic Ketones with
Lithium Aluminum Hydride Partially Decomposed by
(1R,2S)-(-)-N-Methylephedrine and 2-Alkylaminopyridine" Chem. Letters pp.
239-242 (1984).
Kruse, L.I.; Kaiser, C.; DeWolf, W.E.; Finkelstein. J.A.; Frazee, J.S.;
Hilbert, E.L.; Ross, S.T.; Flaim, K.E.; Sawyer, J.L. Some
Benzyl-Substituted Imidazoles, Tirazoles, Tetrazoles, Pyridinethiones, and
Structural Relatives as Multisubstrate Inhibitors of Dopamine
.beta.-Hydroxylase. 4. Structural-Activity Relationships at the Copper
Binding Site, J. Med. Chem. 1990, 33, 781-789.
Kruse, L.I; Kaiser, C.; DeWolf, W.E.; Frazee, J.S.; Erickson, R.W.; Ezekiel
M.; Ohlstein, E.H.; Ruffolo, R.R.; Berkowitz, B.A. Substituted
1-Benzylimidazole-2-thiols as Potent and Orally Active Inhibitors of
Dopamine .beta.-Hydroxylase. J. Med. Chem. 1986, 29, 887-889.
|
Primary Examiner: McKane; Joseph
Attorney, Agent or Firm: Heller Ehrman White & McAuliffe
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of Ser. No. 08/639,387 filed Apr. 29,
1996, now abandoned which is a division of U.S. Ser. No. 08/403,209, filed
Mar. 17, 1995, now U.S. Pat. No. 5,538,988; which is a CIP of Ser. No.
08/233,655, entitled "Process for Making
5-Aminomethyl-1-benzocycloalkyl-1,3-dihydroimidazolethione Derivatives",
filed Apr. 26, 1994 now U.S. Pat. No. 5,458,150 and incorporated herein by
reference.
Claims
We claim:
1. A process for the preparation of a compound of Formula I:
##STR47##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR48##
which process comprises reacting a compound selected from the group
consisting of Formulas 3, 7, 9, 11, and 16 with an appropriate reactant,
wherein Formula 3 is
##STR49##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I, with a dialkyloxyacetaldehyde in the presence of a chemical
reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.3, R.sup.4
and R.sup.5 are each hydro; and wherein Formula 7 is
##STR50##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I, with a a 2,2-dialkyloxyethylamine in the presence of a chemical
reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.3, R.sup.4
and R.sup.5 are each hydro; and wherein Formula 9 is
##STR51##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with a hydrazide of the formula H.sub.2 NHNC(O)R.sup.34 (in
which R.sup.34 is hydro, aminomethyl, (C.sub.1-4)alkylaminomethyl,
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl), or a protected group thereof,
then treating with base and when necessary deprotecting to give a compound
of Formula I in which R.sup.4 is hydro and R.sup.5 is hydro, aminomethyl,
(C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl; and
wherein Formula 11 is
##STR52##
in which each n, t, R.sup.1, R.sup.4 and R.sup.5 are as defined above with
respect to Formula I with a strong base and then sulfurizing to give a
compound of Formula I in which R.sup.3 is hydro; and wherein Formula 16 is
##STR53##
in which R.sup.32 is cyano or (C.sub.1-4)alkyloxycarbonyl and each n, t
and R.sup.1 are as defined above with respect to Formula I with a compound
of the formula R.sup.33 C(O)L in which L is a leaving group and R.sup.33
is hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and then
treating with thiocyanic acid to give a compound of Formula I in which
R.sup.2 is a group of Formula (a) wherein R.sup.3 is hydro, R.sup.4 is
hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and R.sup.5 is
cyano or (C.sub.1-4)alkyloxycarbonyl.
2. A process of claim 1 for the preparation of a compound of Formula I:
##STR54##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR55##
in which: R.sup.4 and R.sup.5 are independently hydro,
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl and R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl;
and the pharmaceutically acceptable salts, individual isomers, and
mixtures of isomers thereof; which process comprises:
(a) reacting a compound of Formula 3:
##STR56##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I, with a dialkyloxyacetaldehyde in the presence of a chemical
reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.3, R.sup.4
and R.sup.5 are each hydro; and
(b) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(c) optionally further alkylating a compound of Formula I in which R.sup.3,
R.sup.4 and R.sup.5 are each hydro with an appropriately N,N-disubstituted
methyleneammonium salt to give a compound of Formula I in which R.sup.3
and R.sup.5 are each hydro and R.sup.4 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(d) optionally further alkylating a compound of Formula I in which R.sup.4
is hydro and R.sup.3 is other than hydro with an appropriately
N,N-disubstituted methyleneammonium salt to give a corresponding compound
of Formula I in which R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(e) optionally protecting a compound of Formula I in which R.sup.3 is hydro
with a thiol protective group, alkylating with an appropriately
N,N-disubstituted methyleneammonium salt and then deprotecting to give a
compound of Formula I in which R.sup.3 and R.sup.4 are each hydro and
R.sup.5 is dimethylamino or in which R.sup.3 is hydro and both R.sup.4 and
R.sup.5 are di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl;
(f) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl to give a compound of Formula I in
which R.sup.3 is 2-carboxyethyl;
(g) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl to give a compound of Formula I in which R.sup.3 is
2-carbamoylethyl;
(h) optionally further de-methylating a compound of Formula I in which
R.sup.1 is methoxy to give a compound of Formula I in which R.sup.1 is
hydroxy;
(i) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(j) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(k) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
3. A process of claim 1 for the preparation of a compound of Formula I:
##STR57##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR58##
in which: R.sup.4 and R.sup.5 are independently hydro,
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl and R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl;
and the pharmaceutically acceptable salts, individual isomers, and
mixtures of isomers thereof; which process comprises:
(a) reacting a compound of Formula 7:
##STR59##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I, with a a 2,2-dialkyloxyethylamine in the presence of a chemical
reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.3, R.sup.4
and R.sup.5 are each hydro; and
(b) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(c) optionally further alkylating a compound of Formula I in which R.sup.3,
R.sup.4 and R.sup.5 are each hydro with an appropriately N,N-disubstituted
methyleneammonium salt to give a compound of Formula I in which R.sup.3
and R.sup.5 are each hydro and R.sup.4 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(d) optionally further alkylating a compound of Formula I in which R.sup.4
is hydro and R.sup.3 is other than hydro with an appropriately
N,N-disubstituted methyleneammonium salt to give a corresponding compound
of Formula I in which R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(e) optionally protecting a compound of Formula I in which R.sup.3 is hydro
with a thiol protective group, alkylating with an appropriately
N,N-disubstituted methyleneammonium salt and then deprotecting to give a
compound of Formula I in which R.sup.3 and R.sup.4 are each hydro and
R.sup.5 is dimethylamino or in which R.sup.3 is hydro and both R.sup.4 and
R.sup.5 are di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl;
(f) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl to give a compound of Formula I in
which R.sup.3 is 2-carboxyethyl;
(g) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl to give a compound of Formula I in which R.sup.3 is
2-carbamoylethyl;
(h) optionally further de-methylating a compound of Formula I in which
R.sup.1 is methoxy to give a compound of Formula I in which R.sup.1 is
hydroxy;
(i) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(j) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(k) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
4. A process of claim 1 for the preparation of a compound of Formula I:
##STR60##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR61##
in which: R.sup.4 and R.sup.5 independently hydro,
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl and R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl;
and the pharmaceutically acceptable salts, individual isomers, and
mixtures of isomers thereof; which process comprises:
(a) reacting a compound of Formula 9:
##STR62##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with a 2,2-dialkyloxyethylamine and then treating with acid to
give a compound of Formula I in which R.sup.3, R.sup.4 and R.sup.5 are
each hydro; and
(b) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(c) optionally further alkylating a compound of Formula I in which R.sup.3,
R.sup.4 and R.sup.5 are each hydro with an appropriately N,N-disubstituted
methyleneammonium salt to give a compound of Formula I in which R.sup.3
and R.sup.5 are each hydro and R.sup.4 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(d) optionally further alkylating a compound of Formula I in which R.sup.4
is hydro and R.sup.3 is other than hydro with an appropriately
N,N-disubstituted methyleneammonium salt to give a corresponding compound
of Formula I in which R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(e) optionally protecting a compound of Formula I in which R.sup.3 is hydro
with a thiol protective group, alkylating with an appropriately
N,N-disubstituted methyleneammonium salt and then deprotecting to give a
compound of Formula I in which R.sup.3 and R.sup.4 are each hydro and
R.sup.5 is di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl or in which R.sup.3 is hydro and both R.sup.4 and
R.sup.5 are di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl;
(f) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl to give a compound of Formula I in
which R.sup.3 is 2-carboxyethyl;
(g) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl to give a compound of Formula I in which R.sup.3 is
2-carbamoylethyl;
(h) optionally further de-methylating a compound of Formula I in which
R.sup.1 is methoxy to give a compound of Formula I in which R.sup.1 is
hydroxy;
(i) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(j) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(k) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
5. A process of claim 1 for the preparation of a compound of Formula I:
##STR63##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR64##
in which R.sup.4 is hydro, R.sup.3 is --(CH.sub.2).sub.q R.sup.9 {in which
q is 0, 1, 2, 3 or 4 and R.sup.9 is carboxy, (C.sub.1-4)alkyloxycarbonyl,
carbamoyl, a group selected from aryl and heteroaryl (which group is
optionally further substituted with one to two substituents independently
selected from hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazo-5-yl,
carboxy and (C.sub.1-4)alkyloxycarbonyl)} and R.sup.5 is hydro or
--NHR.sup.10 {in which R.sup.10 is hydro, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; or R.sup.5 is hydro, R.sup.3 is --(CH.sub.2).sub.q
R.sup.9 (in which q and R.sup.9 are as defined above) and R.sup.4 is
(C.sub.1-4)alkyl, di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, formyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2
NHR.sup.10 (in which R.sup.10 is as defined above); or R.sup.3 is hydro or
--(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are as defined above),
R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14 is
amino, hydroxy(C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino) and R.sup.5 is
cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl, 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl,
--C(O)R.sup.14 (in which R.sup.14 are as defined above), --C(NH)NR.sup.15
R.sup.16 (in which R.sup.15 and R.sup.16 are independently hydro,
(C.sub.1-4)alkyl or trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NR.sup.10
R.sup.17 (in which R.sup.10 is as defined above and R.sup.17 is hydro or
C.sub.1-4)alkyl); or R.sup.3 is --(CH.sub.2).sub.q R.sup.9 (in which q and
R.sup.9 are as defined above) and R.sup.4 and R.sup.5 are dependently
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl
or hydroxymethyl; or hydroxymethyl; and the pharmaceutically acceptable
salts, individual isomers, and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 11:
##STR65##
in which each n, t, R.sup.1, R.sup.4 and R.sup.5 are as defined above
with respect to Formula I with a compound of the formula
L--(CH.sub.2).sub.q R.sup.9, in which L is a leaving group and each q and
R.sup.9 are as defined above with respect to Formula I, and then
sulfurizing to give a compound of Formula I in which R.sup.3 is
--(CH.sub.2).sub.q R.sup.9 ; and
(b) optionally further hydrolyzing a compound of Formula I in which
R.sup.3, R.sup.4 or R.sup.5 is (C.sub.1-4)alkyloxycarbonyl or a group
which is further substituted by a (C.sub.1-4)alkyloxycarbonyl substituent
to give a compound of Formula I in which R.sup.3, R.sup.4 or R.sup.5 is
carboxy or group which is further substituted by a carboxy substituent;
(c) optionally further aminating a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carboxy or a group which is further substituted by a
carboxy substituent to give a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carbamoyl or a group which is further substituted by
a carbamoyl substituent;
(d) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carboxy or a group which is further substituted by a
carboxy group with a (C.sub.1-4) alcohol to give a compound of Formula I
in which R.sup.3, R.sup.4 or R.sup.5 is (C.sub.1-4)alkyloxycarbonyl or a
group that is further substituted by a (C.sub.1-4)alkyloxycarbonyl group;
(e) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.3, R.sup.4 or R.sup.5 is a group selected
from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and hetero(C.sub.1-4)alkyl
(which aroyl, heteroaroyl, aryl and heteroaryl are further substituted
with one to two methoxy substituents) to give a compound of Formula I in
which R.sup.1 is hydroxy and/or R.sup.3, R.sup.4 or R.sup.5 is a group
selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
hetero(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl are
further substituted with one to two hydroxy substituents);
(f) optionally reacting a compound of Formula I in which R.sup.3, R.sup.4
or R.sup.5 is a group selected from aroyl, heteroaroyl,
aryl(C.sub.1-4)alkyl and hetero(C.sub.1-4)alkyl (which aroyl, heteroaroyl,
aryl and heteroaryl are further substituted with a cyano substituent) with
a hydrazoic acid derivative to give a compound of Formula I in which
R.sup.3, R.sup.4 or R.sup.5 is a group selected from aroyl, heteroaroyl,
aryl(C.sub.1-4)alkyl and hetero(C.sub.1-4)alkyl (which aroyl, heteroaroyl,
aryl and heteroaryl are further substituted with a 1H-tetrazol-5-yl
substituent);
(g) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(h) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(i) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
6. A process of claim 1 for the preparation of a compound of Formula I:
##STR66##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR67##
in which: R.sup.4 and R.sup.5 are each hydro and R.sup.3 is --NHR.sup.10
{in which R.sup.10 is hydro, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; and the pharmaceutically acceptable salts,
individual isomers, and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 11:
##STR68##
in which R.sup.4 and R.sup.5 are each hydro and each n, t and R.sup.1 are
as defined above with respect to Formula I with an amino aryl- or
alkylsulfonate and then sulfurizing to give a compound of Formula I in
which R.sup.3 is amino; and
(b) optionally further reacting a compound of Formula I in which R.sup.3 is
amino with an appropriately substituted amidine to give a compound of
Formula I in which R.sup.3 is --NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11
is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is acetyl or
tert-butoxycarbonyl;
(c) optionally further treating a compound of Formula I in which R.sup.3 is
--NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.3 is --NHC(NH)NH.sub.2
;
(d) optionally further acylating a compound of Formula I in which R.sup.3
is amino with an appropriate acylating agent, or a protected derivative
thereof, and then deprotecting when necessary to give a corresponding
compound of Formula I in which R.sup.3 is --NHR.sup.10, wherein R.sup.10
is (C.sub.1-4)alkanonyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(e) optionally further reacting a compound of Formula I in which R.sup.3 is
amino with (C.sub.1-4)alkyl isocyanate to give a compound of Formula I in
which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl);
(f) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a (C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of
Formula I in which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is a group
which is further substituted by a carboxy substituent;
(g) optionally further aminating a compound of Formula I in which R.sup.3
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a carboxy substituent, to give a compound of Formula I in which R.sup.3
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a carbamoyl substituent;
(h) optionally further reacting a compound of Formula I in which R.sup.3 is
--NHR.sup.10, wherein R.sup.10 is a group which is further substituted by
a carboxy substituent, with a (C.sub.1-4)alcohol to give a compound of
Formula I in which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is a group
which is further substituted by a (C.sub.1-4)alkyloxycarbonyl substituent;
(i) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents) to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.3 is
--NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(j) optionally reacting a compound of Formula I in which R.sup.3 is
--NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with a
cyano substituent) with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is a group
selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent);
(k) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(l) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(m) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
7. A process of claim 1 for the preparation of a compound of Formula I:
##STR69##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR70##
in which: R.sup.3 and R.sup.4 are each hydro and R.sup.5 is hydro or
--NHR.sup.10 {in which R.sup.10 is hydro, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; or R.sup.3 and R.sup.5 are each hydro and R.sup.4
is (C.sub.1-4)alkyl, di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, formyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2
NHR.sup.10 (in which R.sup.10 is as defined above); or R.sup.3 is hydro,
R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14 is
amino, hydroxy (C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino) and R.sup.5 is
cyano, hydroxymethyl, 1H-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl, 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl,
--C(O)R.sup.14 (in which R.sup.14 are as defined above), --C(NH)NR.sup.15
R.sup.16 (in which R.sup.15 and R.sup.16 are independently hydro,
(C.sub.1-4)alkyl or trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NR.sup.10
R.sup.17 (in which R.sup.10 is as defined above and R.sup.17 is hydro or
C.sub.1-4)alkyl); or R.sup.3 is hydro and R.sup.4 and R.sup.5 are
dependently di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl or hydroxymethyl; and the pharmaceutically acceptable
salts, individual isomers, and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 11:
##STR71##
in which each n, t, R.sup.1, R.sup.4 and R.sup.5 are as defined above
with respect to Formula I with a strong base and then sulfurizing to give
a compound of Formula I in which R.sup.3 is hydro; and
(b) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(c) optionally further hydrolyzing a compound of Formula I in which
R.sup.3, R.sup.4 or R.sup.5 is (C.sub.1-4)alkyloxycarbonyl or a group
which is further substituted by a (C.sub.1-4)alkyloxycarbonyl substituent
to give a compound of Formula I in which R.sup.3, R.sup.4 or R.sup.5 is
carboxy or group which is further substituted by a carboxy substituent;
(d) optionally further aminating a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carboxy or a group which is further substituted by a
carboxy substituent to give a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carbamoyl or a group which is further substituted by
a carbamoyl substituent;
(e) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.4 or R.sup.5 is carboxy or a group which is further substituted by a
carboxy group with a (C.sub.1-4)alcohol to give a compound of Formula I in
which R.sup.3, R.sup.4 or R.sup.5 (C.sub.1-4)alkyloxycarbonyl or a group
that is further substituted by a (C.sub.1-4)alkyloxycarbonyl group;
(f) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.4 or R.sup.5 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4 alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl is further substituted with one to
two methoxy substituents) to give a compound of Formula I in which R.sup.1
is hydroxy and/or R.sup.4 or R.sup.5 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4 alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl is further substituted with one to
two hydroxy substituents);
(g) optionally reacting a compound of Formula I in which R.sup.4 or R.sup.5
is a group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4 alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
is further substituted with a cyano substituent) with a hydrazoic acid
derivative to give a compound of Formula I in which R.sup.4 or R.sup.5 is
a group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4 alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
is further substituted with a 1H-tetrazol-5-yl substituent);
(h) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(i) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(j) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
8. A process of claim 1 for the preparation of a compound of Formula I:
##STR72##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR73##
in which: R.sup.4 is hydro, R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl and
R.sup.5 is --NHR.sup.10 {in which R.sup.10 is hydro, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; and the pharmaceutically acceptable salts,
individual isomers, and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 9:
##STR74##
in which each n, t and R.sup.1 are as defined above with respect to
formula I with aminoacetonitrile hydrochloride and then treating with base
to give a compound of Formula I in which R.sup.3 and R.sup.4 are each
hydro and R.sup.5 is amino; and
(b) optionally further reacting a compound of Formula I in which R.sup.5 is
amino with an appropriately substituted amidine to give a compound of
Formula I in which R.sup.5 is --NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11
is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is acetyl or
tert-butoxycarbonyl;
(c) optionally further treating a compound of Formula I in which R.sup.5 is
--NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.5 is --NHC(NH)NH.sub.2
;
(d) optionally further acylating a compound of Formula I in which R.sup.5
is amino with an appropriate acylating agent, or a protected derivative
thereof, and then deprotecting when necessary to give a corresponding
compound of Formula I in which R.sup.5 is --NHR.sup.10, wherein R.sup.10
is (C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(e) optionally further reacting a compound of Formula I in which R.sup.5 is
amino with (C.sub.1-4)alkyl isocyanate to give a compound of Formula I in
which R.sup.3 is --NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl;
(f) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(g) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.5 is --NHR.sup.10,
wherein R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of Formula I
in which R.sup.3 is 2-carboxyethyl and/or R.sup.3 is --NHR.sup.10, wherein
R.sup.10 is a group which is further substituted by a carboxy substituent;
(h) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl and/or R.sup.5 is --NHR.sup.10, wherein R.sup.10 is a
group which is further substituted by a carboxy substituent, to give a
compound of Formula I in which R.sup.3 is 2-carbamoylethyl and/or R.sup.5
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a carbamoyl substituent;
(i) optionally further reacting a compound of Formula I in which R.sup.3 is
2-carboxyethyl and/or R.sup.3 is --NHR.sup.10, wherein R.sup.10 is a group
which is further substituted by a carboxy substituent, with a
(C.sub.1-4)alcohol to give a compound of Formula I in which R.sup.3 is
2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.5 is --NHR.sup.10, wherein
R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent;
(j) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.5 is --NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteroaryl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents) to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.5 is
--NHR.sup.10, wherein R.sup.10 is a group selected frown aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(k) optionally reacting a compound of Formula I in which R.sup.5 is
--NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl is further substituted with a
cyano substituent) with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.5 is --NHR.sup.10, wherein R.sup.10 is a group
selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
is further substituted with a 1H-tetrazol-5-yl substituent);
(l) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(m) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(n) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
9. A process of claim 1 for the preparation of a compound of Formula I:
##STR75##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR76##
in which: R.sup.3 is hydro, 2-(C.sub.1-4)alkyloxycarbonylethyl,
2-carboxymethyl or 2-carbamoylethyl;
R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14 is
amino, hydroxy(C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino); and
R.sup.5 is cyano, hydroxymethyl, 1H-tetrazol-5-yl,
4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, --C(O)R.sup.14 (in which R.sup.14
are as defined above), --C(NH)NR.sup.15 R.sup.16 (in which R.sup.15 and
R.sup.16 are independently hydro, (C.sub.1-4)alkyl or
trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NHR.sup.10 {in which R.sup.10 is
hydro, (C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, or a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituent independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl)}; or R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl and
R.sup.4 and R.sup.5 are dependently di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;
(a) reacting a compound of Formula 16:
##STR77##
in which R.sup.32 is cyano or (C.sub.1-4)alkyloxycarbonyl and each n, t
and R.sup.1 are as defined above with respect to Formula I with a compound
of the formula R.sup.33 C(O)L in which L is a leaving group and R.sup.33
is hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and then
treating with thiocyanic acid to give a compound of Formula I in which
R.sup.2 is a group of Formula (a) wherein R.sup.3 is hydro, R.sup.4 is
hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and R.sup.3 is
cyano or (C.sub.1-4)alkyloxycarbonyl; and
(b) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with a hydrazoic acid derivative to give a compound of Formula I in
which R.sup.5 is 1H-tetrazol-5-yl;
(c) optionally further hydrolyzing a compound of Formula I in which R.sup.5
is cyano to give a compound of Formula I in which R.sup.5 is carbamoyl;
(d) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with ethylenediamine to give a compound of Formula I in which
R.sup.5 is 4,5-dihydroimidazol-2-yl;
(e) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with a compound of the formula (CH.sub.3).sub.2 AlNR.sup.15 R.sup.16
to give a compound of Formula I in which R.sup.5 is --C(NH)NR.sup.15
R.sup.16, wherein R.sup.15 and R.sup.16 are as defined above with respect
to Formula I;
(f) optionally further reducing a compound of Formula I in which R.sup.5 is
cyano to give a compound of Formula I in which R.sup.5 is aminomethyl;
(g) optionally further reducing a compound of Formula I in which R.sup.5 or
both R.sup.4 and R.sup.5 are ethoxycarbonyl to give a compound of Formula
I in which R.sup.5 or both R.sup.4 and R.sup.5 are hydroxymethyl;
(h) optionally further converting a compound of Formula I in which R.sup.5
is hydroxymethyl to a compound of Formula 28:
##STR78##
in which L is a leaving group and n, t and R.sup.1 are as defined in the
Summary of the Invention with respect to Formula I and reacting the
compound of Formula 27 with an amine of the formula HNR.sup.36 R.sup.37 in
which R.sup.36 and R.sup.37 are independently hydro, (C.sub.1-4)alkyl or
together are --(CH.sub.2).sub.4 --; --(CH.sub.2).sub.5 --;
--(CH.sub.2).sub.2 O(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.2 NR.sup.38
(CH.sub.2).sub.2 --, wherein R.sup.38 is hydro or (C.sub.1-4)alkyl, to
give a compound of Formula I in which R.sup.5 is aminomethyl,
(C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl, 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl;
(i) optionally further reacting a compound of Formula I in which R.sup.5 or
both R.sup.4 and R.sup.5 are carboxy, or an acid derivative thereof, with
an appropriate amine or thiol to give a compound of Formula I in which
R.sup.5 or both R.sup.4 and R.sup.5 are 1H-tetrazol-5-ylcarbamoyl,
2-(dimethylamino)ethylcarbamoyl, 4-methylpiperazin-1-ylcarbonyl or
2-(dimethylamino)ethylmercapto;
(j) optionally further reacting a compound of Formula I in which R.sup.5 is
aminomethyl with an appropriately substituted amidine to give a compound
of Formula I in which R.sup.5 is --CH.sub.2 NHC(NR.sup.11)NHR.sup.12,
wherein R.sup.11 is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is
acetyl or tert-butoxycarbonyl;
(k) optionally further treating a compound of Formula I in which R.sup.5 is
--CH.sub.2 NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.5 is --CH.sub.2
NHC(NH)NH.sub.2 ;
(l) optionally further acylating a compound of Formula I in which R.sup.5
is aminomethyl with an appropriate acylating agent, or a protected
derivative thereof, and then deprotecting when necessary to give a
corresponding compound of Formula I in which R.sup.5 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaryl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(m) optionally further reacting a compound of Formula I in which R.sup.5 is
aminomethyl with (C.sub.1-4)alkyl isocyanate to give a compound of Formula
I in which R.sup.5 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl;
(n) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(o) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.5 is
(C.sub.1-4)alkyloxycarbonyl or a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of Formula I
in which R.sup.3 is 2-carboxyethyl and/or R.sup.5 is carboxy or a group
which is further substituted by a carboxy substituent;
(p) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl and/or R.sup.5 is carboxy or a group which is further
substituted by a carboxy substituent, to give a compound of Formula I in
which R.sup.3 is 2-carbamoylethyl and/or R.sup.5 is carbamoyl or a group
which is further substituted by a carbamoyl substituent;
(q) optionally further reacting a compound of Formula I in which R.sup.3 is
2-carboxyethyl and/or R.sup.5 is carboxy or a group which is further
substituted by a carboxy substituent, with a (C.sub.1-4)alcohol to give a
compound of Formula I in which R.sup.3 is
2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.5 is
(C.sub.1-4)alkyloxycarbonyl or a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent;
(r) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.5 is --CH.sub.2 NHR.sup.10, wherein R.sup.10
is a group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents), to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.5 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(s) optionally reacting a compound of Formula I in which R.sup.5 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with a
cyano substituent), with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.5 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent);
(t) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(u) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(v) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
10. A process of claim 1 for the preparation of a compound of Formula I:
##STR79##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (a):
##STR80##
in which: R.sup.5 is hydro, R.sup.3 is hydro,
2-(C.sub.1-4)alkyloxycarbonylethyl, 2-carboxyethyl or 2-carbamoylethyl and
R.sup.5 is formyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2 NHR.sup.10 {in
which R.sup.10 is hydro, (C.sub.1-4)alkyl, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, carboxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkyloxycarbonyl(C.sub.1-4)alkyl, carbamoyl(C.sub.1-4)alkyl, a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are optionally further substituted with one to two substituents
independently selected from hydroxy, (C.sub.1-4)alkyloxy, cyano,
1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11)NHR.sup.12 (in which R.sup.11 and R.sup.12 are independently
hydro, acetyl or tert-butoxycarbonyl)}; and the pharmaceutically
acceptable salts, individual isomers, and mixtures of isomer thereof;
which process comprises:
(a) reacting a compound of Formula 9:
##STR81##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I, with D-(+)-glucosamine and then oxidizing to give a compound of
Formula I in which R.sup.4 is formyl;
(b) optionally further reacting a compound of Formula I in which R.sup.4 is
formyl with hydroxylamine hydrochloride and then reducing to give a
compound of Formula I in which R.sup.4 is aminomethyl;
(c) optionally further alkylating a compound of Formula I in which R.sup.5
is formyl to give a compound of Formula I in which R.sup.4 is
1-hydroxy(C.sub.1-4)alkyl;
(d) optionally further reacting a compound of Formula I in which R.sup.4 is
formyl with an amine of the formula NH.sub.2 R.sup.10, wherein R.sup.10 is
as defined above with respect to Formula I, in the presence of a chemical
reducing agent or catalytic hydrogenation to give a corresponding compound
of Formula I in which R.sup.4 is --CH.sub.2 NHR.sup.10 ;
(e) optionally further reacting a compound of Formula I in which R.sup.4 is
aminomethyl with an appropriately substituted amidine to give a compound
of Formula I in which R.sup.4 is --CH.sub.2 NHC(NR.sup.11)NHR.sup.12,
wherein R.sup.11 is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is
acetyl or tert-butoxycarbonyl;
(f) optionally further treating a compound of Formula I in which R.sup.4 is
--CH.sub.2 NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.4 is --CH.sub.2
NHC(NH)NH.sub.2 ;
(g) optionally further acylating a compound of Formula I in which R.sup.4
is aminomethyl with an appropriate acylating agent, or a protected
derivative thereof, and then deprotecting when necessary to give a
corresponding compound of Formula I in which R.sup.4 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(h) optionally further reacting a compound of Formula I in which R.sup.4 is
aminomethyl with (C.sub.1-4)alkyl isocyanate to give a compound of Formula
I in which R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl;
(i) optionally further reacting a compound of Formula I in which R.sup.3 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.3 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(j) optionally further hydrolyzing a compound of Formula I in which R.sup.3
is 2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.4 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of Formula I
in which R.sup.3 is 2-carboxyethyl and/or R.sup.4 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
carboxy substituent;
(k) optionally further aminating a compound of Formula I in which R.sup.3
is 2-carboxyethyl and/or R.sup.4 is --CH.sub.2 NHR.sup.10, wherein
R.sup.10 is a group which is further substituted by a carboxy substituent,
to give a compound of Formula I in which R.sup.3 is 2-carbamoylethyl
and/or R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group which
is further substituted by a carbamoyl substituent;
(l) optionally further reacting a compound of Formula I in which R.sup.3 is
2-carboxyethyl and/or R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10
is a group which is further substituted by a carboxy substituent, with a
(C.sub.1-4)alcohol to give a compound of Formula I in which R.sup.3 is
2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.4 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent;
(m) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10
is a group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents) to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.4 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(n) optionally reacting a compound of Formula I in which R.sup.4 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with a
cyano substituent) with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent);
(o) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(p) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(q) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
11. A process for the preparation of a compound of Formula I:
##STR82##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (b):
##STR83##
in which: R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl and
R.sup.7 is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NR.sup.10 R.sup.17
{in which R.sup.10 is hydro, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl) and R.sup.17 is hydro or C.sub.1-4)alkyl); and the
pharmaceutically acceptable salts, individual isomers, and mixtures of
isomers thereof; which process comprises:
(a) reacting a compound of Formula 9:
##STR84##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with a hydrazide of the formula H.sub.2 C(O)R.sup.34 (in which
R.sup.34 is hydro, aminomethyl, (C.sub.1-4)alkylaminomethyl,
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl), or a protected derivative
thereof, then treating with base and when necessary deprotecting to give a
compound of Formula I in which R.sup.6 is hydro and R.sup.7 is hydro,
aminomethyl, (C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl;
(b) optionally further reacting a compound of Formula I in which R.sup.7 is
aminomethyl with an appropriately substituted amidine to give a compound
of Formula I in which R.sup.4 is --CH.sub.2 NHC(NR.sup.11)NHR.sup.12,
wherein R.sup.11 is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is
acetyl or tert-butoxycarbonyl;
(c) optionally further treating a compound of Formula I in which R.sup.7 is
--CH.sub.2 NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.4 is --CH.sub.2
NHC(NH)NH.sub.2 ;
(d) optionally further acylating a compound of Formula I in which R.sup.7
is aminomethyl with an appropriate acylating agent, or a protected
derivative thereof, and then deprotecting when necessary to give a
corresponding compound of Formula I in which R.sup.7 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(e) optionally further reacting a compound of Formula I in which R.sup.7 is
aminomethyl with (C.sub.1-4)alkyl isocyanate to give a compound of Formula
I in which R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl);
(f) optionally further reacting a compound of Formula I in which R.sup.6 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.6 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(g) optionally further hydrolyzing a compound of Formula I in which R.sup.6
is 2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.7 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of Formula I
in which R.sup.6 is 2-carboxyethyl and/or R.sup.7 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
carboxy substituent;
(h) optionally further aminating a compound of Formula I in which R.sup.6
is 2-carboxyethyl and/or R.sup.7 is --CH.sub.2 NHR.sup.10, wherein
R.sup.10 is a group which is further substituted by a carboxy substituent,
to give a compound of Formula I in which R.sup.6 is 2-carbamoylethyl
and/or R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group which
is further substituted by a carbamoyl substituent;
(i) optionally further reacting a compound of Formula I in which R.sup.6 is
2-carboxyethyl and/or R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10
is a group which is further substituted by a carboxy substituent, with a
(C.sub.1-4)alcohol to give a compound of Formula I in which R.sup.6 is
2-(C.sub.1-4)alkyloxycarbonylethyl and/or R.sup.7 is --CH.sub.2
NHR.sup.10, wherein R.sup.10 is a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent;
(j) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy and/or in which R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10
is a group selected from aroyl, heteraroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents) to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.7 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteraroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(k) optionally reacting a compound of Formula I in which R.sup.7 is
--CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteraroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with a
cyano substituent) with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteraroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent);
(l) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(m) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(n) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
12. A process for the preparation of a compound of Formula I:
##STR85##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (c):
##STR86##
in which: R.sup.8 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl; and the pharmaceutically acceptable
salts, individual isomers and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 24:
##STR87##
in which n, t and R.sup.1 are as defined above with respect to Formula I
with an isothiocyanate and then treating with base to give a compound of
Formula I in which R.sup.8 is hydro; and
(b) optionally further reacting a compound of Formula I in which R.sup.8 is
hydro with (C.sub.1-4)alkyl acrylate to give a compound of Formula I in
which R.sup.8 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(c) optionally further hydrolyzing a compound of Formula I in which R.sup.8
is 2-(C.sub.1-4)alkyloxycarbonylethyl to give a compound of Formula I in
which R.sup.8 is 2-carboxyethyl;
(d) optionally further aminating a compound of Formula I in which R.sup.8
is 2-carboxyethyl to give a compound of Formula I in which R.sup.8 is
2-carbamoylethyl;
(e) optionally further reacting a compound of Formula I in which R.sup.8 is
2-carboxyethyl with a (C.sub.1-4)alcohol to give a compound of Formula I
in which R.sup.8 is 2-(C.sub.1-4)alkyloxycarbonylethyl;
(f) optionally de-methylating a compound of Formula I in which R.sup.1 is
methoxy to give a compound of Formula I in which R.sup.1 is hydroxy;
(g) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(h) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(i) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
13. A process for the preparation of a compound of Formula I:
##STR88##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group of Formula (c):
##STR89##
in which: R.sup.8 is --NHR.sup.10 {in which R.sup.10 is hydro,
(C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; and the pharmaceutically acceptable salts,
individual isomers, and mixtures of isomers thereof; which process
comprises:
(a) reacting a compound of Formula 5:
##STR90##
in which n, t and R.sup.1 are as defined above with respect to Formula I
with 1,2,4-triazol-4-ylamino and then sulfurizing to give a compound of
Formula I in which R.sup.8 is amino; and
(b) optionally further reacting a compound of Formula I in which R.sup.8 is
amino with an appropriately substituted amidine to give a compound of
Formula I in which R.sup.8 is --NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11
is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is acetyl or
tert-butoxycarbonyl;
(c) optionally further treating a compound of Formula I in which R.sup.8 is
--NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl, with
acid to give a compound of Formula I in which R.sup.8 is --NHC(NH)NH.sub.2
; (d) optionally further acylating a compound of Formula I in which
R.sup.8 is amino with an appropriate acylating agent, or a protected
derivative thereof, and then deprotecting when necessary to give a
corresponding compound of Formula I in which R.sup.8 is --NHR.sup.10,
wherein R.sup.10 is (C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl,
carbamoyl, (C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(e) optionally further hydrolyzing a compound of Formula I in which R.sup.8
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a (C.sub.1-4)alkyloxycarbonyl substituent, to give a compound of
Formula I in which R.sup.8 is --NHR.sup.10, wherein R.sup.10 is a group
which is further substituted by a carboxy substituent;
(f) optionally further aminating a compound of Formula I in which R.sup.8
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a carboxy substituent, to give a compound of Formula I in which R.sup.8
is --NHR.sup.10, wherein R.sup.10 is a group which is further substituted
by a carbamoyl substituent;
(g) optionally further reacting a compound of Formula I in which R.sup.8 is
--NHR.sup.10, wherein R.sup.10 is a group which is further substituted by
a carboxy substituent, with a (C.sub.1-4)alcohol to give a compound of
Formula I in which R.sup.8 is --NHR.sup.10, wherein R.sup.10 is a group
which is further substituted by a (C.sub.1-4)alkyloxycarbonyl substituent;
(h) optionally de-methylating a compound of Formula I in which R.sup.10 is
methoxy and/or in which R.sup.8 is --NHR.sup.10, wherein R.sup.10 is a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two methoxy substituents) to give a
compound of Formula I in which R.sup.1 is hydroxy and/or R.sup.8 is
--NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents);
(i) optionally reacting a compound of Formula I in which R.sup.8 is
--NHR.sup.10, wherein R.sup.10 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with a
cyano substituent) with a hydrazoic acid derivative to give a compound of
Formula I in which R.sup.8 is --NHR.sup.10, wherein R.sup.10 is a group
selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent);
(j) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(k) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(l) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
14. A process for the preparation of a compound of Formula II:
##STR91##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.18 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formula (d), (e) or (f):
##STR92##
in which: R.sup.20 is hydro, R.sup.19 is hydro or --(CH.sub.2).sub.q
R.sup.9 {in which q is 0, 1, 2, 3 or 4 and R.sup.9 is carboxy,
(C.sub.1-4)alkyloxycarbonyl, carbamoyl or a group selected from aryl and
heteroaryl (which group is optionally further substituted with one to two
substituents independently selected from hydroxy, (C.sub.1-4)alkyloxy,
cyano, 1H-tetrazo-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl)} and
R.sup.21 is --NR.sup.25 R.sup.26 (in which R.sup.25 is hydro or
(C.sub.1-4)alkyl and R.sup.26 is L-alanyl, L-arginyl, L-asparaginyl,
L-.alpha.-aspartyl, L-.beta.-aspartyl, L-cysteinyl, L-glutaminyl,
L-.alpha.-glutamyl, L-.gamma.-glutamyl,
N-(C.sub.1-4)alkanoyl-L-.alpha.-glutamyl,
N-(C.sub.1-4)alkanoyl-L-.gamma.-glutamyl, glycyl, L-histidyl, L-isoleucyl,
L-leucyl, L-lysyl, L-methionyl, L-ornithinyl, L-phenylalanyl, L-prolyl,
L-seryl, L-threonyl, L-tryptophyl, L-tyrosyl, L-valyl,
1-amino-cyclopropylcarbonyl, 1-aminocyclobutylcarbonyl,
1-aminocyclopentylcarbonyl or 1-aminocyclohexylcarbonyl); or R.sup.20 and
R.sup.21 are each hydro and R.sup.19 is --NR.sup.25 R.sup.26 (in which
R.sup.25 and R.sup.26 are as defined above); or R.sup.21 is hydro,
R.sup.19 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9
are as defined above) and R.sup.20 is --CH.sub.2 R.sup.25 R.sup.26 (in
which R.sup.25 and R.sup.26 are as defined above); or R.sup.19 is hydro or
--(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are as defined above),
R.sup.20 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14
is amino, hydroxy(C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino) and R.sup.21 is
--CH.sub.2 NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26 is as
defined above); and
R.sup.22 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.23 is --CH.sub.2 NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26
are as defined above); and
R.sup.24 is --NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26 are as
defined above); and the pharmaceutically acceptable salts, individual
isomers and mixtures of isomers thereof, which process comprises:
(a) reacting a protected derivative of an L-amino acid with a compound of
Formula I:
##STR93##
or a pharmaceutically acceptable salt, an individual isomer or a mixture
of isomers thereof, in which each n, t and R.sup.1 are as defined above
with respect to Formula II; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (a), (b) and (c):
##STR94##
in which: R.sup.4 is hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9
(in which q and R.sup.9 are as defined above) and
R.sup.5 is --NHR.sup.10 (in which R.sup.10 is hydro or (C.sub.1-4)alkyl);
or R.sup.4 and R.sup.5 are each hydro and
R.sup.3 is --NHR.sup.10 (in which R.sup.10 is as defined above); or R.sup.5
is hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and
R.sup.9 are as defined above) and R.sup.4 is --CH.sub.2 NHR.sup.10 (in
which R.sup.10 is as defined above); or R.sup.3 is hydro or
--(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are as defined above),
R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14 is
amino, hydroxy(C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino) and R.sup.5 is
--CH.sub.2 NHR.sup.10 (in which R.sup.10 is as defined above); and
R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.7 is --CH.sub.2 NHR.sup.10 (in which R.sup.10 is as defined above);
and
R.sup.8 is --NHR.sup.10 (in which R.sup.10 is as defined above); and
(b) optionally further reacting the corresponding non-salt form of a
compound of Formula II with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(c) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula II with a suitable base
or acid, respectively, to give the free acid or free base; and
(d) optionally further separating a mixture of stereoisomers of a compound
of Formula II to give a single stereoisomer.
15. A process for the preparation of a compound of Formula III:
##STR95##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.27 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (g), (h) and (i):
##STR96##
in which: R.sup.4 is hydro and R.sup.5 is hydro or --NHR.sup.10 {in which
R.sup.10 is hydro, (C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl,
carbamoyl, (C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; or R.sup.5 is hydro and R.sup.4 is
(C.sub.1-4)alkyl, di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2 NHR.sup.13
{in which R.sup.13 is hydro, (C.sub.1-4)alkyl, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, carboxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkyloxycarbonyl (C.sub.1-4)alkyl, carbamoyl (C.sub.1-4)alkyl,
a group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are optionally further substituted with one to two substituents
independently selected from hydroxy, (C.sub.1-4)alkyloxy, cyano,
1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11) NHR.sup.12 (in which R.sup.11 and R.sup.12 are as defined
above)}; or R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which
R.sup.14 is amino, hydroxy(C.sub.1-4)alkyloxy,
2-(dimethylamino)ethylamino, 4-methylpiperazin-1-yl,
2-(dimethylamino)ethylmercapto, 4-(methylsulfonylamino)anilino or
1H-tetrazol-5-ylamino) and R.sup.5 is hydroxymethyl, 1H-tetrazol-5-yl,
4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, --C(O)R.sup.14 (in which R.sup.14
are as defined above), --C(NH)NR.sup.15 R.sup.16 (in which R.sup.15 and
R.sup.16 are independently hydro, (C.sub.1-4)alkyl or
trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NR.sup.17 (in which R.sup.10 is
as defined above and R.sup.17 is hydro or C.sub.1-4)alkyl); or R.sup.4 and
R.sup.5 are dependently di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;
R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.7 is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NR.sup.10 R.sup.7 (in
which R.sup.10 and R.sup.17 are as defined above); and
R.sup.28 is (C.sub.1-4)alkyl {which alkyl is further substituted by one to
two substituents independently selected from --N(R.sup.29).sub.2,
--C(O)OR.sup.30, --PO(OR.sup.30).sub.2, --SO.sub.3 NHR.sup.30, --SO.sub.2
NHR.sup.30 and --OR.sup.30 (in which each R.sup.29 is independently hydro,
acetyl or trifluoroacetyl and each R.sup.30 is independently hydro or
(C.sub.1-4)alkyl)}; and the pharmaceutically acceptable salts, individual
isomers, and mixtures of isomers thereof, which process comprises:
(a) reacting a compound of Formula 47:
##STR97##
or a protected derivative thereof, in which R.sup.28 is as defined above
with respect to Formula III, with a compound of Formula I:
##STR98##
or a pharmaceutically acceptable salt, an individual isomer or a mixture
of isomers thereof, in which n, t and R.sup.1 are as defined above and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (a), (b) and (c):
##STR99##
in which R.sup.3, R.sup.7 and R.sup.8 are hydro and R.sup.4, R.sup.5 and
R.sup.6 are as defined above with respect to Formula III; and when
necessary deprotecting; and
(b) optionally reacting the corresponding non-salt form of a compound of
Formula III with a pharmaceutically acceptable inorganic or organic acid
or base to give a pharmaceutically acceptable salt;
(c) optionally reacting the corresponding acid addition salt or base
addition salt form of a compound of Formula III with a suitable base or
acid, respectively, to give the free acid or free base; and
(d) optionally separating a mixture of stereoisomers of a compound of
Formula III to give a single stereoisomer.
16. A compound of the formula:
##STR100##
namely (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine.
17. A process for the preparation of a S-enantiomer of Formula 3(a):
##STR101##
in which: t is 0, 1, 2 or 3; and
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy;
which process comprises:
(a) reducing, in the presence of 2S-dimethylamino-1R-phenylpropanol and
2-ethylaminopyridine, a compound of Formula 7(b):
##STR102##
to give an (R)-enantiomer of Formula 6(c):
##STR103##
(b) treating the (R)-enantiomer of Formula 6(c) with methanesulfonyl
chloride and then reacting with an azide salt to give a (S)-enantiomer of
Formula 4(a):
##STR104##
and (c) reducing.
18. The process of claim 17 in which t is 2 and R.sup.1 is fluoro at the 5-
and 7-position.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel benzocycloalkylazolethione dopamine
.beta.-hydroxylase inhibitors and the methods of using and preparing such
inhibitors.
2. Description of the Field
Dopamine is a catecholamine neurotransmitter found predominately, along
with specific dopaminergic receptors, in the central nervous system.
Norepinephrine is a circulating catecholamine, which acts at discrete
adrenergic receptors in peripheral systems. Dopamine .beta.-hydroxylase
(DBH) catalyzes the conversion of dopemine to norepinephrine and is found
in both central and peripheral sympathetic neurons. Inhibition of DBH
concurrently elevates dopamine levels by blocking its metabolism and
reduces norepinephrine levels by blocking its synthesis. Thus, drugs which
inhibit DBH are useful for treating diseases associated with reduced
dopamine levels (e.g., Parkinson's disease) and for treating diseases
associated with elevated norepinephrine levels (e.g., hypertension,
congestive heart failure, etc.). Fusaric acid, a DBH inhibitor, decreases
the tremors and other abnormalities associated with Parkinson's disease.
Fusaric acid also reduces blood pressure in hypertensive patients;
however, release of norepinephrine from the adrenal gland and a resultant
tachycardia is also observed. Other more selective DBH inhibitors are
known but often possess disadvantageous effects.
SUMMARY OF THE INVENTION
The present invention relates to a compound of Formula I:
##STR1##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (a), (b) and (c):
##STR2##
in which: R.sup.4 is hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9
{in which q is 0, 1, 2, 3 or 4 and R.sup.9 is carboxy,
(C.sub.1-4)alkyloxycarbonyl, carbamoyl or a group selected from aryl and
heteroaryl (which group is optionally further substituted with one to two
substituents independently selected from hydroxy, (C.sub.1-4)alkyloxy,
cyano, 1H-tetrazo-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl)} and
R.sup.5 is hydro or --NHR.sup.10 {in which R.sup.10 is hydro,
(C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; or R.sup.4 and R.sup.5 are each hydro and R.sup.3
is --NHR.sup.10 (in which R.sup.10 is as defined above); or R.sup.5 is
hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and
R.sup.9 are as defined above) and R.sup.4 is (C.sub.1-4)alkyl,
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
formyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2 NHR.sup.13 {in which
R.sup.13 is hydro, (C.sub.1-4)alkyl, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, carboxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkyloxycarbonyl(C.sub.1-4)alkyl, carbamoyl(C.sub.1-4)alkyl, a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are optionally further substituted with one to two substituents
independently selected from hydroxy, (C.sub.1-4)alkyloxy, cyano,
1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11)NHR.sup.12 (in which R.sup.11 and R.sup.12 are as defined
above)}; or R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and
R.sup.9 are as defined above), R.sup.4 is hydro, (C.sub.1-4)alkyl or
--C(O)R.sup.14 (in which R.sup.14 is amino, hydroxy (C.sub.1-4)alkyloxy,
2-(dimethylamino)ethylamino, 4-methylpiperazin-1-yl,
2-(dimethylamino)ethylmercapto, 4-(methylsulfonylamino)anilino or
1H-tetrazol-5-ylamino) and R.sup.5 is cyano, hydroxymethyl,
1H-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, --C(O)R.sup.14 (in which R.sup.14
are as defined above), --C(NH)NR.sup.15 R.sup.16 (in which R.sup.15 and
R.sup.16 are independently hydro, (C.sub.1-4)alkyl or
trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 R.sup.10 R.sup.17 (in which
R.sup.10 is as defined above and R.sup.17 is hydro or C.sub.1-4)alkyl); or
R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are
as defined above) and R.sup.4 and R.sup.5 are dependently
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl
or hydroxymethyl;
R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.7 is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NR.sup.10 R.sup.17
(in which R.sup.10 and R.sup.17 are as defined above); and
R.sup.8 is hydro, 2-carboxyethyl, 2-carbamoylethyl,
2-(C.sub.1-4)alkyloxycarbonylethyl or --NHR.sup.10 (in which R.sup.10 are
as defined above); and the pharmaceutically acceptable salts, individual
isomers, and mixtures of isomers thereof.
Another aspect of this invention is a pharmaceutical composition comprising
a therapeutically effective amount of a compound of Formula I or an
individual isomer, a mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof, in combination with one or more
pharmaceutically acceptable excipients.
Another aspect of this invention is a method for treating a condition
capable of amelioration by inhibition of dopamine .beta.-hydroxylase in an
animal in need thereof, which method comprises administering to such
animal a therapeutically effective amount of a compound of Formula I, or
of an individual isomer, mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof.
Another aspect of this invention is the processes for preparing compounds
of Formula I and is set forth in "Detailed Description of the Invention".
Another aspect of this invention relates to a compound of Formula II:
##STR3##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.18 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (d), (e) and (f):
##STR4##
in which: R.sup.20 is hydro, R.sup.19 is hydro or --(CH.sub.2).sub.q
R.sup.9 {in which q is 0, 1, 2, 3 or 4 and R.sup.9 is carboxy,
(C.sub.1-4)alkyloxycarbonyl, carbamoyl or a group selected from aryl and
heteroaryl (which group is optionally further substituted with one to two
substituents independently selected from hydroxy, (C.sub.1-4)alkyloxy,
cyano, 1H-tetrazo-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl)} and
R.sup.21 is --NR.sup.25 R.sup.26 (in which R.sup.25 is hydro or
(C.sub.1-4)alkyl and R.sup.26 is L-alanyl, L-arginyl, L-asparaginyl,
L-.alpha.-aspartyl, L-.beta.-aspartyl, L-cysteinyl, L-glutaminyl,
L-.alpha.-glutamyl, L-.gamma.-glutamyl,
N-(C.sub.1-4)alkanoyl-L-.alpha.-glutamyl,
N-(C.sub.1-4)alkanoyl-L-.gamma.-glutamyl, glycyl, L-histidyl, L-isoleucyl,
L-leucyl, L-lysyl, L-methionyl, L-ornithinyl, L-phenylalanyl, L-prolyl,
L-seryl, L-threonyl, L-tryptophyl, L-tyrosyl, L-valyl,
1-amino-cyclopropylcarbonyl, 1- aminocyclobutylcarbonyl,
1-aminocyclopentylcarbonyl or 1-aminocyclohexylcarbonyl); or R.sup.20 and
R.sup.21 are each hydro and R.sup.19 is --NR.sup.25 R.sup.26 (in which
R.sup.25 and R.sup.26 are as defined above); or R.sup.21 is hydro,
R.sup.19 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9
are as defined above) and R.sup.20 is --CH.sub.2 NR.sup.25 R.sup.26 (in
which R.sup.25 and R.sup.26 are as defined above); or R.sup.19 is hydro or
--(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are as defined above),
R.sup.20 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which R.sup.14
is amino, hydroxy (C.sub.1-4)alkyloxy, 2-(dimethylamino)ethylamino,
4-methylpiperazin-1-yl, 2-(dimethylamino)ethylmercapto,
4-(methylsulfonylamino)anilino or 1H-tetrazol-5-ylamino) and R.sup.21 is
--CH.sub.2 NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26 is as
defined above); and
R.sup.22 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.23 is --CH.sub.2 NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26
are as defined above); and
R.sup.24 is --NR.sup.25 R.sup.26 (in which R.sup.25 and R.sup.26 are as
defined above); and the
pharmaceutically acceptable salts, individual isomers, and mixtures of
isomers thereof.
Another aspect of this invention is a pharmaceutical composition comprising
a therapeutically effective amount of a compound of Formula II, or of an
individual isomer, a mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof, in combination with one or more
pharmaceutically acceptable excipients.
Another aspect of this invention is a method for treating a condition
capable of amelioration by inhibition of dopemine .beta.-hydroxylase in an
animal in need thereof, which method comprises administering to such
animal a therapeutically effective amount of a compound of Formula II, or
of an individual isomer, mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof.
Another aspect of this invention is the processes for preparing compounds
of Formula II and is set forth in "Detailed Description of the Invention".
Another aspect of this invention relates to a compound of Formula III:
##STR5##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.27 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (g), (h) and (i):
##STR6##
in which: R.sup.4 is hydro and R.sup.5 is hydro or --NHR.sup.10 {in which
R.sup.10 is hydro, (C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl,
carbamoyl, (C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, a group selected from aroyl
and heteroaroyl (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
hydroxy, (C.sub.1-4)alkyloxy, cyano, 1H-tetrazol-5-yl, carboxy and
(C.sub.1-4)alkyloxycarbonyl) or --C(NR.sup.11)NHR.sup.12 (in which
R.sup.11 and R.sup.12 are independently hydro, acetyl or
tert-butoxycarbonyl)}; or R.sup.5 is hydro and R.sup.4 is
(C.sub.1-4)alkyl, di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2 NHR.sup.13
{in which R.sup.13 is hydro, (C.sub.1-4)alkyl, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, carboxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkyloxycarbonyl(C.sub.1-4)alkyl, carbamoyl(C.sub.1-4)alkyl, a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are optionally further substituted with one to two substituents
independently selected from hydroxy, (C.sub.1-4)alkyloxy, cyano,
1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11)NHR.sup.12 (in which R.sup.11 and R.sup.12 are as defined
above)}; or R.sup.4 is hydro, (C.sub.1-4)alkyl or --C(O)R.sup.14 (in which
R.sup.14 is amino, hydroxy (C.sub.1-4)alkyloxy,
2-(dimethylamino)ethylamino, 4-methylpiperazin-1-yl,
2-(dimethylamino)ethylmercapto, 4-(methylsulfonylamino)anilino or
1H-tetrazol-5-ylamino) and R.sup.5 is hydroxymethyl, 1H-tetrazol-5-yl,
4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, --C(O)R.sup.14 (in which R.sup.14
are as defined above), --C(NH)NR.sup.15 R.sup.16 (in which R.sup.15 and
R.sup.16 are independently hydro, (C.sub.1-4)alkyl or
trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NR.sup.10 R.sup.17 (in which
R.sup.10 is as defined above and R.sup.17 is hydro or C.sub.1-4)alkyl); or
R.sup.4 and R.sup.5 are dependently di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl or hydroxymethyl;
R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.7 is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NR.sup.10 R.sup.17
(in which R.sup.10 and R.sup.17 are as defined above); and
R.sup.28 is (C.sub.2-6)alkyl {which alkyl is further substituted by one to
two substituents independently selected from --N(R.sup.29).sub.2,
--C(O)OR.sup.30, --PO(OR.sup.30).sub.2, --SO.sub.3 R.sup.30, --SO.sub.2
NHR.sup.30 and --OR.sup.30 (in which each R.sup.29 is independently hydro,
acetyl or trifluoroacetyl and each R.sup.30 is independently hydro or
(C.sub.1-5)alkyl)}; and the pharmaceutically acceptable salts, individual
isomers, and mixtures of isomers thereof.
Another aspect of this invention is a pharmaceutical composition comprising
a therapeutically effective amount of a compound of Formula III, or of an
individual isomer, a mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof, in combination with one or more
pharmaceutically acceptable excipients.
Another aspect of this invention is a method for treating a condition
capable of amelioration by inhibition of dopamine .beta.-hydroxylase in an
animal in need thereof, which method comprises administering to such
animal a therapeutically effective amount of a compound of Formula III, or
of an individual isomer, mixture of isomers, or the pharmaceutically
acceptable salt or salts thereof.
Another aspect of this invention is the processes for preparing compounds
of Formula III and is set forth in "Detailed Description of the
Invention".
Another aspect of this invention is a compound of the formula:
##STR7##
namely (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine.
Another aspect of this invention is the processes for preparing
(S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine and is set forth
in "Detailed Description of the Invention".
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
As used herein:
"Alkyl" means a straight or branched saturated hydrocarbon radical having
from one to the number of carbon atoms designated (e.g., (C.sub.1-4)alkyl
includes the radicals methyl, ethyl, prop-1-yl, prop-2-yl, but-1-yl,
but-2-yl, 2-methylpropyl and 1,1-dimethylethyl).
"Trifluoroalkyl" means a radical alkyl as defined above having from one to
the number of carbon atoms designated wherein is contained a
trifluoromethyl group (e.g., trifluoro(C.sub.1-4)alkyl includes
trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoroprop-1-yl,
1,1,1-trifluoroprop-2-yl, etc.).
"Alkyloxy" means the radical --OR, wherein R is alkyl having from one to
the number of carbon atoms designated (e.g., (C.sub.1-4)alkyloxy includes
the radicals methoxy, ethoxy, prop-1-yloxy, prop-2-yloxy, but-1-yloxy,
but-2-yloxy, 2-methylprop-1-yloxy and 2-methylprop-2-yloxy).
"Aryl", as in aryl or aryl(C.sub.1-4)alkyl, means an organic radical
derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms and
includes monocyclic or condensed carbocyclic aromatic rings (e.g., phenyl,
naphthyl, anthracenyl, phenanthrenyl, etc.) optionally further substituted
with one to two substituents independently selected from halo and cyano.
"Aroyl" means the radical --C(O)R, wherein R is aryl as defined above
(e.g., benzoyl, etc.).
"Heteroaryl", as in heteroaryl or heteroaryl(C.sub.1-4)alkyl, means an
organic radical derived from an aromatic hydrocarbon containing 5 to 14
atoms, 1 to 5 of which are hetero atoms chosen from N, O, or S, and
includes monocyclic, condensed heterocyclic and condensed carbocyclic and
heterocyclic aromatic rings (e.g., thienyl, furyl, pyrrolyl, pyrimidinyl,
isoxazolyl, oxazolyl, indolyl, benzo›b!thienyl, isobenzofuranyl, purinyl,
isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl,
pyrazinyl, etc.) optionally further substituted with one to two
substituents independently selected from halo and cyano.
"Heteroaroyl" means the radical --C(O)R, wherein R is heteroaryl as defined
above (e.g., nicotinoyl, 2-furanoyl, picolinoyl, etc.).
"Carbamoyl", as in carbamoyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl or carbamoyl(C.sub.1-4)alkyl, means
aminocarbonyl.
"Alkanoyl" means the radical --C(O)R having from one to the number of
carbon atoms designated (e.g., formyl, acetyl, propionyl, butyryl, etc.)
"Halo" means fluoro, chloro or bromo.
"Leaving group" has the meaning conventionally associated with it in
synthetic organic chemistry, i.e., an atom or group displaceable under
alkylating conditions, and includes halo and alkane- or arenesulfonyloxy,
such as mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy,
trifluoromethanesufonyloxy and tosyloxy, and the like.
"Animal" includes humans, non-human mammals, e.g., dogs, cats, rabbits,
cattle, horses, sheep, goats, swine, and deer, and non-mammals, e.g.,
birds and the like.
"Disease" specifically includes any unhealthy condition of an animal or
part thereof and includes an unhealthy condition which may be caused by,
or incident to, medical or veterinary therapy applied to that animal,
i.e., the "side effects" of such therapy.
"Pharmaceutically acceptable" means that which is useful in preparing a
pharmaceutical composition that is generally safe, non-toxic and neither
biologically nor otherwise undesirable and includes that which is
acceptable for veterinary use as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" means salts which are pharmaceutically
acceptable, as defined above, and which possess the desired
pharmacological activity. Such salts include acid addition salts formed
with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, and the like; or with organic acids
such as formic acid, acetic acid, propionic acid, hexanoic acid, heptanoic
acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic
acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic
acid, p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo›2.2.2!oct-2-ene-1-carboxylic acid, glucoheptonic acid,
4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic
acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric
acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid,
stearic acid, muconic acid, and the like.
Pharmaceutically acceptable salts also include base addition salts which
may be formed when acidic protons present are capable of reacting with
inorganic or organic bases. Acceptable inorganic bases include sodium
hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and
calcium hydroxide. Acceptable organic bases include ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the
like.
"Therapeutically effective amount" means that amount which, when
administered to an animal for treating a disease, is sufficient to effect
such treatment for the disease.
"Treating" or "treatment" of a disease includes:
(1) preventing the disease from occurring in an animal which may be
predisposed to the disease but does not yet experience or display symptoms
of the disease,
(2) inhibiting the disease, i.e., arresting its development, or
(3) relieving the disease, i.e., causing regression of the disease.
Compounds of Formula I in which R.sup.3, R.sup.5 or R.sup.8 is amino or in
which R.sup.4, R.sup.5 or R.sup.7 is aminomethyl can react with amino
acids to give compounds of Formula II. Suitable amino acids include
L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine,
L-glutamine, L-glutamic acid, glycine, L-histidine, L-isoleucine,
L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine,
L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine or L-valine and
achiral cyclo amino acids such as 1-amino-1-cyclopropanecarboxylic acid,
1-amino-1-cyclobutanecarboxylic acid, 1-amino-1-cyclopentanecarboxylic
(cycloleucine) or 1-amino-1-cyclohexanecarboxylic acid. The amino acid
group imparts hydrophilic properties to the molecule. The hydrophilicity
promotes the water solubility of the molecule. The amide bond is
subsequently cleaved in vivo by proteolysis. Thus, compounds of Formula II
are water soluble prodrugs for compounds of Formula I in which R.sup.3,
R.sup.5 or R.sup.8 is amino or in which R.sup.4, R.sup.5 or R.sup.7 is
aminomethyl.
Compounds of Formula I in which R.sup.3, R.sup.6 or R.sup.8 is hydro can
react to form a dithio linkage with a (C.sub.2-6)alkyl group which is
substituted by one to two substituents independentyl selected from
--N(R.sup.29).sub.2, --C(O)OR.sup.30, --PO(OR.sup.30).sub.2, --SO.sub.3
R.sup.30, --SO.sub.2 NHR.sup.30 and --OR.sup.30, in which each R.sup.29 is
independently hydro, acetyl or trifluoroacetyl and each R.sup.30 is
independently hydro or (C.sub.1-5)alkyl. The substituted alkyl group
imparts hydrophilic properties to the molecule. The hydrophilicity
promotes the water solubility of the molecule. The dithio linkage is
subsequently cleaved in vivo by chemical, enzymatic or metabolic
transformation. Thus, compounds of Formula III are water soluble prodrugs
for compounds of Formula I in which R.sup.3, R.sup.6 or R.sup.7 is hydro.
The compounds of Formulae I, II and III are benzocycloalkylazolethione
derivatives wherein the benzocycloalkyl portion of the molecule is of the
general formula:
##STR8##
and are more specifically defined as follows: (1) a group in which n is 0
and the monovalent carbon is at the 1- or 2-position (i.e., .alpha.- or
.beta.-position) having the formula:
##STR9##
is referred to as optionally substituted indan-1-yl or indan-2-yl,
respectively;
(2) a group in which n is 1 and the monovalent carbon is at the 1- or
2-position (i.e., .alpha.- or .beta.-position) having the formula:
##STR10##
is referred to as optionally substituted
1,2,3,4-tetrahydronaphthalen-1-yl or 1,2,3,4-tetrahydronaphthalen-2-yl,
respectively; and
(3) a group in which n is 2 and the monovalent carbon is at the 5-, 6- or
7-position having the formula:
##STR11##
is referred to as optionally substituted
6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl,
6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl or
6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl, respectively.
The monovalent carbon of the benzocycloalkyl group may be a chiral center.
Thus, compounds of Formula I and certain compounds used in the synthesis
thereof may exist as either one of a pair of enantiomers of opposite
chirality or as a mixture of such enantiomers. Compounds of Formulae II
and III each contain one or two chiral centers. Compounds of Formulae II
and III containing two chiral centers have two pairs of enantiomers (i.e.,
four diastereomers) and may exist as any one of the enantiomers or as a
mixture thereof. The enantiomers are characterized by the absolute
configuration of their chiral centers and described by the R- and
S-sequencing rules of Cahn, Ingold and Prelog. When two chiral centers are
present, the configuration of each chiral center is assigned an R or S
descriptor as appropriate. Conventions for stereochemical nomenclature,
methods for the determination of stereochemistry and the separation of
stereoisomers are well-known in the art (e.g., see "Advanced Organic
Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New York, 1985).
Unless indicated otherwise, the illustration, description or naming of a
particular chiral compound of Formulae I, II, III, 1-6, 8-32, 44-46 and 48
in the specification or in the claims is intended to include both
individual enantiomers and the mixtures, racemic or otherwise, thereof.
The azolethione portion of the molecule (i.e., the R.sup.2, R.sup.18 and
R.sup.27 groups of compounds of Formulae I, II and III, respectively) is
an imidazolethione or triazolethione group. For example, R.sup.2 is
specifically defined as follows:
(1) a group of Formula (a):
##STR12##
referred to as 1,3-dihydroimidazole-2-thione when forming the parent name
or 2-thioxo-2,3-dihydro-1H-imidazolyl when forming a prefix to the parent
name;
(2) a group of Formula (b):
##STR13##
referred to as 2,4-dihydro›1,2,4!triazole-3-thione when forming the
parent name or 5-thioxo-4,5-dihydro-1H-›1,2,4!triazolyl when forming a
prefix to the parent name; or
(3) a group of Formula (c):
##STR14##
referred to as 2,4-dihydro›1,2,4!triazole-3-thione when forming the
parent name or 5-thioxo-4,5-dihydro-1H-›1,2,4!triazolyl when forming a
prefix to the parent name.
Certain R.sup.2 and R.sup.18 groups exist in tautomeric equilibrium between
thioxo and mercapto tautomers (e.g., a group of Formula (a) in which
R.sup.3 is hydro). Compounds of Formula I or II which contain groups that
can exist as either tautomer are named, illustrated or otherwise described
in this application as thiones or thioxo substituted derivatives. However,
it is to be understood that the mercapto tautomers are encompassed by such
names, illustrations and descriptions as well.
The compounds of Formulae I, II and III are named by AUTONOM Version 1.0 by
Beilstein-Institut and Springer-Verlag Berlin Heidelberg, a fully
automatic computerized system for assigning IUPAC systematic nomenclature
directly from the structural diagrams of organic compounds. For example, a
compound of Formula I in which n is 1, t is 0 and R.sup.2 is attached at
the .beta.-position and is a group of Formula (a), i.e., of the formula:
##STR15##
is named
5-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2
-thione when R.sup.5 is aminomethyl and is named
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-
carboxylic acid when R.sup.5 is carboxy.
A compound of Formula I in which n is 1, t is 0 and R.sup.2 is attached at
the .beta.-position and is a group of Formula (b) is named
5-aminomethyl-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,4-dihydro›1,2,4!tria
zole-3-thione when R.sup.6 is aminomethyl.
A compound of Formula I in which n is 1, t is 0 and R.sup.2 is attached at
the .beta.-position and is a group of Formula (c) is named
4-amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triazole-3
-thione when R.sup.7 is amino and is named
N-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-thioxo-4,5-dihydro›1,2,4!triazo
l-4-yl!acetamide when R.sup.7 is acetylamino.
A compound of Formula II in which n is 1, t is 0 and R.sup.18 is attached
at the .beta.-position and is a group of Formula (d), wherein R.sup.21 is
L-.alpha.-aspartylaminomethyl, i.e., of the formula:
##STR16##
is named 3S
-amino-N-›3-(1,2,3,4-tetrahydronaphthalen-2S-yl)-2-thioxo-2,3-dihydro-1H-i
midazol-4-ylmethyl!succinamic acid.
A compound of Formula III in which n is 1, t is 0 and R.sup.27 is attached
at the .beta.-position and is a group of Formula (g), wherein R.sup.5 is
aminomethyl and R.sup.28 is 2-amino-2-carboxyethyl, i.e., of the formula:
##STR17##
is named
2-amino-3-›5-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazol
-2-yldisulfanyl!propionic acid.
Presently Preferred Embodiments:
While the breadth of compounds which are intended by the invention is as
set forth in the Summary of the Invention, certain compounds of Formulae
I, II and III are preferred. Preferred compounds of Formula I are those in
which R.sup.2 is a group of Formula (a) and are designated as compounds of
Formula I(a). Preferred compounds of Formula I(a) are those in which
R.sup.2 is attached to the benzocycloalkyl portion of the molecule at the
.beta.-position, preferably wherein n is 0 or 1 and R.sup.5 is
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 HR.sup.10. Most
preferred compounds of Formula I(a) are those in which R.sup.2 is attached
at the .beta.-position, n is 1, t is 2, each R.sup.1 is fluoro, preferably
at the 5- and 7-position, and R.sup.5 is --CH.sub.2 NHR.sup.10, in which
R.sup.10 is hydro, carbamoyl or (C.sub.1-4)alkanoyl, preferably acetyl,
particularly the S-enantiomer thereof.
Compounds of Formula I in which R.sup.2 is a group of Formula (b) are
designated as compounds of Formula I(b). Preferred compounds of Formula
I(b) are those in which R.sup.2 is attached at the .beta.-position,
preferably wherein n is 0 or 1 and R.sup.7 is
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NHR.sup.10. Most
preferred compounds of Formula I(b) are those in which R.sup.2 is attached
at the .beta.-position, n is 1, t is 2, each R.sup.1 is fluoro, preferably
at the 5- and 7-positions, and R.sup.6 is di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl, 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2
NHR.sup.10, particularly the S-enantiomer thereof.
Compounds of Formula I in which R.sup.2 is a group of Formula (c) are
designated compounds of Formula I(c). Preferred compounds of Formula I(c)
are those in which R.sup.2 is attached at the .beta.-position, preferably
wherein n is 0 or 1 and R.sup.8 is --NH.sub.2. Most preferred compounds of
Formula I(c) are those in which R.sup.2 is attached at the
.beta.-position, n is 1, t is 2, each R.sup.1 is fluoro, preferably at the
5- and 7-position, and R.sup.8 is --NH.sub.2, particularly the
S-enantiomer thereof.
Preferred compounds of Formula II are those in which R.sup.18 is a group of
Formula (d) and is attached at the .beta.-position, preferably wherein n
is 0 or 1 and R.sup.21 is --CH.sub.2 NHR.sup.26. Most preferred are
compounds of Formula II in which R.sup.18 is a group of Formula (d) and is
attached at the .beta.-position, n is 0 or 1, t is 2, each R.sup.1 is
fluoro, preferably at the 5- and 7-position, and R.sup.21 is --CH.sub.2
NHR.sup.26, preferably wherein R.sup.26 is arginyl, .alpha.-aspartyl,
.beta.-aspartyl, histidyl or ornithinyl.
Preferred compounds of Formula III are those in which R.sup.27 is a group
of Formula (g) and is attached at the .beta.-position, preferably wherein
n is 0 or 1 and R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl, 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2
NHR.sup.10. Most preferred are compounds of Formula III in which R.sup.27
is a group of Formula (g) and is attached at the .beta.-position, n is 0
or 1, t is 2, each R.sup.1 is fluoro, preferably at the 5- and 7-position,
R.sup.5 is di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NHR.sup.10 and
R.sup.28 is a group selected from ethyl, 1,1-dimethylethyl and propyl
(which group is further substituted with one to two substituents
independently selected from carboxy, methoxycarbonyl, amino and
trifluoroacetylamino, preferably wherein R.sup.28 is
(R)-2-amino-2-methoxycarbonylethyl, (R)-2-amino-2-carboxyethyl,
(R)-2-trifluoroacetylamino-2-methoxycarbonylethyl, 2-aminoethyl,
(S)-2-amino-2-carboxy-1,1-dimethylethyl or 3-amino-3-carboxyprop-1-yl.
Pharmacology and Utility:
The compounds of the invention are inhibitors of dopamine
.beta.-hydroxylase. Accordingly, the compounds of the invention are useful
in treating diseases capable of amelioration by inhibition of dopamine
.beta.-hydroxylase. For example, in as much as the compounds of the
invention block norepinephrine biosynthesis, they are useful in treating
diseases caused or exacerbated by a hypersympathetic condition. In
particular, because the compounds of the invention are peripheral
vasodilators, they are useful as afterload reducing agents in treating
congestive heart failure. Furthermore, because the compounds of the
invention reduce norepinephrine levels, they alleviate the damaging
effects to the myocardium that hypersympatheic activity produces in
congestive heart failure. Thus, the compounds of the invention are
particularly useful for treating congestive heart failure because they
produce an initial improvement in cardiac output by reducing afterload and
a sustained improvement in cardiac function by reducing norepinephrine
levels in the myocardial tissue.
The dopamine .beta.-hydroxylase inhibitor properties of test compounds can
be determined by an art-recognized in vitro assay which relies upon the
DBH-catalyzed conversion of tyramine to octopamine and the inhibition of
DBH activity by test compounds and is described specifically in Example
53. Dopamine .beta.-hydroxylase inhibitor properties of test compounds
also can be determined by an art-recognized in vivo assay which relies
upon dopamine and norepinephrine tissue concentrations and the effect of
the test compounds thereon (e.g., see author: B. A. Berkowitz et al., 1988
J. Pharm. Exp Ther. 245, 850-857) and is described specifically in Example
54. The blood pressure lowering properties of test compounds can be
determined by an in vivo assay utilizing spontaneously hypertensive rats
which is described specifically in Example 55.
Administration and Pharmaceutical Composition:
In general, compounds of the invention will be administered in
therapeutically effective amounts via any of the usual and acceptable
modes known in the art, either singly or in combination with another
compound of the invention or with another therapeutic agent. A
therapeutically effective amount may vary widely depending on the severity
of the disease, the age and relative health of the subject, the potency of
the compound used and other factors. A therapeutically effective amount
may range from approximately 0.1 milligram per Kg (mg/Kg) body weight per
day to 30 mg/Kg body weight per day. Preferably the amount will be
approximately 1.0 to 10 mg/Kg/day. Therefore, a therapeutically effective
amount for a 70 Kg human may range from 7.0 to 2100 mg/day, preferably 70
to 700 mg/day.
One of ordinary skill in the art of treating such diseases will be able to
ascertain a therapeutically effective amount of a compound of the
invention for a given disease without undue experimentation and in
reliance upon personal knowledge and the disclosure of this application.
In general, compounds of the invention will be administered as
pharmaceutical compositions by one of the following routes: oral, systemic
(e.g., transdermal, intranasal or by suppository) or parenteral (e.g.,
intramuscular, intravenous or subcutaneous). Compositions can take the
form of tablets, pills, capsules, semisolids, powders, sustained release
formulations, solutions, suspensions, elixirs, aerosols, or any other
appropriate composition and are comprised of, in general, a compound of
the invention in combination with at least one pharmaceutically acceptable
excipient. Acceptable excipients are non-toxic, aid administration, and do
not adversely affect the therapeutic benefit of the compound of Formula I.
Such excipient may be any solid, liquid, semisolid or, in the case of an
aerosol composition, gaseous excipient that is generally available to one
of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose,
lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium
stearate, sodium stearate, glycerol monostearate, sodium chloride, dried
skim milk, and the like. Liquid and semisolid excipients may be selected
from water, ethanol, glycerol, propylene glycol and various oils,
including those of petroleum, animal, vegetable or synthetic origin (e.g.,
peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid
carriers, particularly for injectable solutions, include water, saline,
aqueous dextrose and glycols.
Compressed gases may be used to disperse the compound of the invention in
aerosol form. Inert gases suitable for this purpose are nitrogen, carbon
dioxide, nitrous oxide, etc. Other suitable pharmaceutical carriers and
their formulations are described in A. R. Alfonso Remington's
Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing
Company.
The amount of a compound of the invention in the composition may vary
widely depending upon the type of formulation, size of a unit dosage, kind
of excipients and other factors known to those of skill in the art of
pharmaceutical sciences. In general, the final composition will comprise
from 10% w to 90% w of the compound, preferably 25% w to 75% w, with the
remainder being the excipient or excipients.
Preferably the pharmaceutical composition is administered in a single unit
dosage form for continuous treatment or in a single unit dosage form ad
libitum when relief of symptoms is specifically required. Representative
pharmaceutical formulations containing a compound of Formula I are
described in Example 56.
CHEMISTRY
Compounds of Formula I(a):
A method for making compounds of Formula I(a) in which R.sup.3, R.sup.4 and
R.sup.5 are each hydro is depicted by the following Reaction Scheme I:
##STR18##
in which L is a leaving group, R.sup.31 is alkyl, preferably methyl or
ethyl, and each n, t and R.sup.1 are as defined in the Summary of the
Invention with respect to Formula I.
Compounds of Formula I(a) in which R.sup.3, R.sup.4 and R.sup.5 are each
hydro (Formula 1) can be prepared by reacting a compound of Formula 2 with
thiocyanic acid in a suitable solvent, typically an alcohol (e.g.,
methanol, ethanol, any appropriate mixture of suitable alcohols, etc.) and
preferably methanol. The reaction is carried out with potassium
thiocyanate in the presence of aqueous acid (e.g., dilute hydrochloric
acid, phosphoric acid or sulfuric acid, etc.) at 50.degree. to 100.degree.
C., typically at 70.degree. to 90.degree. C. and preferably at
approximately 80.degree. C., and requires 1 to 5 hours.
Compounds of Formula 2 can be prepared by reductive amination of a
dialkyloxyacetaldehyde, preferably dimethoxyacetaldehyde or
diethoxyacetaldehyde, with a compound of Formula 3. The reductive
amination is carried out in the presence of a chemical reducing agent
(e.g., sodium cyanoborohydride, sodium borohydride, etc.) or catalytic
hydrogenation (e.g., H.sub.2, palladium on carbon, H.sub.2, Raney.RTM.
nickel, etc.) in a suitable solvent (e.g., methanol, ethanol, ethyl
acetate, any appropriate mixture of suitable solvents, etc.). Optionally
water is removed from the reaction mixture by standard methods (e.g., with
drying agents such as molecular selves or by azeotroping). Further details
of the reaction steps set forth in this and the preceding paragraph are
provided in Example 9, infra. Alternatively, compounds of Formula 2 can be
prepared by reductive amination of a compound of Formula 7:
##STR19##
with a 2,2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine or
2,2-diethoxyethylamine (for further details see Example 12, infra.).
Compounds of Formula 3 can be obtained commercially or can be prepared by
reacting a compound of Formula 5 with an appropriate azide salt (e.g.,
sodium azide, lithium azide, etc.) in a suitable solvent (e.g., dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), etc.) to give an azide of
Formula 4 and then reducing. The reaction with the azide salt is carried
out at 50.degree. to 90.degree. C., typically at 50.degree. to 60.degree.
C. and preferably at approximately 50.degree. C., and requires 12 to 18
hours. Reduction of the compound of Formula 4 can be effected by catalytic
hydrogenation (e.g., H.sub.2, 10% palladium on carbon; or H.sub.2,
platinum on carbon, etc.) in a suitable solvent (e.g., ethyl acetate,
ethanol, etc.). Further details of the reaction steps set forth in this
paragraph are provided in Example 8, infra.
Compounds of Formula 5 are prepared by treating a compound of Formula 6
with an appropriate agent to create leaving group L. For example,
compounds of Formula 5 in which L is mesyloxy can be prepared by reacting
a compound of Formula 6 with methanesulfonyl chloride in a suitable
solvent (e.g., diethyl ether, tetrahydrofuran (THF), methylene chloride,
any appropriate mixture of suitable solvents, etc.). The reaction is
carried out in the presence of triethylamine at -20.degree. to 5.degree.
C., typically at -15.degree. to -5.degree. C. and preferably at
approximately -10.degree. C., and requires 3 to 15 hours (for further
details see Example 7, infra.).
An alternative method for making compounds of Formula I(a) in which
R.sup.3, R.sup.4 and R.sup.5 are each hydro is depicted by the following
Reaction Scheme II:
##STR20##
in which R.sup.31 is alkyl, preferably methyl or ethyl, and each n, t and
R.sup.1 are as defined in the Summary of the Invention with respect to
Formula I.
Compounds of Formula I(a) in which R.sup.3, R.sup.4 and R.sup.5 are each
hydro can be prepared by reacting a compound of Formula 9 with a
2,2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine or
2,2-diethoxyethylamine, in a suitable solvent (e.g., DMF, DMSO,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), etc.) to give a
compound of Formula 8 and then treating the compound of Formula 8 with
acid (e.g., hydrochloric acid) to effect ring closure. The reaction with
the amine is carried out at 20.degree. to 90.degree. C., typically at
70.degree. to 90.degree. C. and preferably at approximately 85.degree. C.,
and requires 1 to 2.5 hours. The treatment with acid and resultant ring
closure is carried out at 20.degree. to 90.degree. C., typically at
70.degree. to 85.degree. C. and preferably at approximately 80.degree. C.,
and requires 3 to 72 hours. Further details of the reaction steps set
forth in this paragraph are provided in Example 11, infra.
Compounds of Formula 9 can be prepared by reacting a compound of Formula 3
with 1,1'-thiocarbonyldiimidazole in a suitable solvent (e.g., ethyl
acetate, acetonitrile, acetone, methylene chloride, any appropriate
mixture of suitable solvents, etc.). The reaction is carried out at
0.degree. to 50.degree. C., typically at 10.degree. to 30.degree. and
preferably at approximately 20.degree. C., and requires 3 to 18 hours (for
further details see Example 10, infra.).
A method for making compounds of Formula I(a) in which R.sup.3 is
--(CH.sub.2).sub.q R.sup.9 is depicted by the following Reaction Scheme
III:
##STR21##
in which L is a leaving group and each n, t, R.sup.1, R.sup.4, R.sup.5 and
R.sup.9 are as defined in the Summary of the Invention with respect to
Formula I.
Compounds of Formula I(a) in which R.sup.3 is --(CH.sub.2).sub.q R.sup.9
(Formula 10) can be prepared by alkylating a compound of Formula 11 with
an alkylating agent of the formula L--(CH.sub.2).sub.q R.sup.9 to give the
corresponding imidazolium salt and then sulfurizing. The alkylation is
carried out in a suitable solvent (e.g., acetonitrile, DMF, THF, any
appropriate mixture of suitable solvents), preferably acetonitrile or DMF,
at 0.degree. to 160.degree. C., typically at approximately 25.degree. C.
to reflux, and requires 1 to 16 hours. The sulfurization is carried out
with lac sulfur in a suitable mild base (e.g., triethylamine, pyridine,
any appropriate mixture of mild bases, etc., preferably a mixture of
triethylamine and pyridine) at 50.degree. to 125.degree. C., typically
80.degree. to 100.degree. C. and preferably at approximately 90.degree.
C., and requires 1 to 8 hours. In a similar fashion, compounds of Formula
I(a) in which R.sup.3 is amino can be prepared by reacting a compound of
Formula 11 with an amino aryl or alkylsulfonate (e.g.,
O-mesitylenesulfonylhydroxylamine, O-methanesulfonylhydroxylamine or
O-hydroxylaminesulfonic acid) to give the corresponding 3-aminoimidazolium
salt and then sulfurizing. The reaction with the sulfonate is carried out
in a suitable solvent (e.g., acetonitrile, methylene chloride, THF, any
appropriate mixture of suitable solvents, etc., preferably acetonitrile)
at 0.degree. to 40.degree. C., typically at 10.degree. to 30.degree. C.
and preferably at approximately 20.degree. C., and requires 0.5 to 18
hours. Further details of the reaction steps set forth in this paragraph
are provided in Example 15, infra.
Compounds of Formula 11 can be prepared by reacting the corresponding
compound of Formula 5 with an appropriately substituted imidazole in a
suitable solvent (e.g., DMF, DMSO, acetonitrile, etc.). The reaction is
carried out at 50.degree. to 100.degree. C., preferably at approximately
85.degree. C., and requires 8 to 24 hours (for further details see Example
13, infra.). In a similar fashion, compounds of Formula 11 in which n is 1
and the imidazole portion of the molecule is attached at the
.beta.-position can be prepared by reacting an appropriately substituted
2-bromo-1,2,3,4-tetrahydronapththalen-1-one with an appropriately
substituted imidazole and then reducing. The reduction can be carried out
by catalytic hydrogenation (e.g., H.sub.2, palladium hydroxide) in a
suitable acidic solvent (e.g., sulfuric acid, acetic acid, any appropriate
mixture of acids, etc.) at 15 to 100 psi, typically at 40 to 60 psi and
preferably at approximately 50 psi, and requires 1 to 24 hours.
Alternatively, compounds of Formula 11 can be prepared by treating a
corresponding of Formula I with Raney.RTM. nickel. The treatment with
Raney.RTM. nickel is carried out in a suitable solvent (e.g., ethanol,
methanol, acetic acid, water, any appropriate mixture of suitable
solvents, etc. preferably ethanol) at 0.degree. to 100.degree. C.,
typically at 25.degree. to 80.degree. C. and preferably at approximately
80.degree., and requires 0.25 to 4 hours (for further details see Example
14, infra.).
Compounds of Formula I(a) in which R.sup.3 and R.sup.4 are hydro and
R.sup.5 is di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl can be prepared by alkylating a compound of Formula
11 in which R.sup.4 and R.sup.5 are both hydro with an appropriately
N,N-disubstituted methyleneammonium salt (e.g., a
N,N-di(C.sub.1-4)alkylmethyleneammonium salt such as
N,N-dimethylmethyleneammonium chloride, N,N-diethylmethyleneammonium
chloride and the like, 1-methylenepiperidinium chloride, a
4-methylenemorpholinium chloride, etc.) and then sulfurizing. The
alkylation is carried out in a suitable solvent (e.g., DMF, DMPU,
acetonitrile, any appropriate mixture of suitable solvents, etc.,
preferably DMF) at 50.degree. to 100.degree. C., typically at 80.degree.
to 100.degree. C. and preferably at approximately 95.degree. C., and
requires 4 to 18 hours.
Compounds of Formula I(a) in which R.sup.3 is hydro can be prepared by
reacting a compound of Formula 11 with a strong base (e.g.,
n-butyllithium, lithium diisopropylamide (LDA), etc.) in a suitable
solvent (e.g., 1,2-dimethoxyethane, THF, 2-methoxyethyl ether, etc.) to
give the corresponding 2-imidazolide and then sulfurizing. The reaction
with the base is carried out by cooling a solution of a compound of
Formula 12 to between 0.degree. and -78.degree. C., typically to between
-50.degree. and -78.degree. and preferably to approximately -78.degree.
C., adding the base and then allowing the reaction to proceed for 0.25 to
3 hours. The sulfurization is carried out at 0.degree. to -78.degree. C.,
typically at -50.degree. and -78.degree. and preferably at approximately
-78.degree. C., and requires 2 to 18 hours. Further details of the
reaction steps set forth in this paragraph are provided in Example 16,
infra.
A method for making compounds of Formula I(a) in which R.sup.3 and R.sup.4
are hydro and R.sup.5 is amino is depicted by the following Reaction
Scheme IV:
##STR22##
in which each n, t and R.sup.1 are as defined in the Summary of the
Invention with respect to Formula I.
Compounds of Formula I(a) in which R.sup.3 and R.sup.4 are hydro and
R.sup.5 is amino (Formula 12) can be prepared by treating a compound of
Formula 13 with an alkali base (e.g., potassium hydroxide or sodium
hydroxide) to effect rearrangement. The treatment with base and attendant
rearrangement is carried out at 0.degree. to 40.degree. C., typically at
10.degree. to 30.degree. C. and preferably at approximately 20.degree. C.,
and requires 0.1 to 2 hours.
Compounds of Formula 13 can be prepared by reacting a compound of Formula 9
with aminoacetonitrile hydrochloride in a suitable solvent (e.g.,
triethylemine, triethylamine in acetonitrile, dimethylformamide, or
dimethylsulfoxide). The reaction is carried out at 20.degree. to
100.degree. C., typically at 10.degree. to 30.degree. C. and preferably at
approximately 20.degree. C., and requires 12 to 24 hours. Further details
of the reaction steps set forth in this paragraph and the preceding
paragraph are provided in Example 17, infra.
A method for making confounds of Formula I(a) in which R.sup.3 is hydro,
R.sup.4 is hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and
R.sup.5 is cyano or (C.sub.1-4)alkyloxycarbonyl is depicted by the
following Reaction Scheme V:
##STR23##
in which L is a leaving group (e.g., halo, alkyloxy, acyloxy, aryloxy,
etc.), R.sup.32 is cyano or (C.sub.1-4)alkyloxycarbonyl), R.sup.33 is
hydro, (C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and each n, t and
R.sup.1 are as defined in the Summary of the Invention with respect to
Formula I.
Compounds of Formula I(a) in which R.sup.3 is hydro, R.sup.4 is hydro,
(C.sub.1-4)alkyl or (C.sub.1-4)alkyloxycarbonyl and R.sup.5 is cyano or
(C.sub.1-4)alkyloxycarbonyl (Formula 14) can be prepared by reacting a
compound of Formula 16 with a compound of the formula R.sup.33 C(O)L to
give a compound of Formula 15 and then reacting the compound of Formula 15
with thiocyanic acid. The reaction with the compound of the formula
R.sup.33 C(O)L is carried out in the presence of base (e.g., potassium
tert-butoxide, LDA, etc.) and in a suitable solvent (e.g., THF,
1,2-diethoxyethane, diethyl ether, any appropriate mixture of suitable
solvents, etc.).
For example, a compound of Formula 15 in which R.sup.4 is hydro can be
prepared by reacting a compound of Formula 16 with an alkyl or arylformate
(e.g., ethyl formate, phenyl formate, etc.) in the presence of potassium
tert-butoxide. The reaction with the formate is carried out at -40.degree.
to 65.degree. C., typically at -30.degree. to 0.degree. C. and preferably
at approximately -15.degree. C., and requires 3 to 24 hours (for further
details see Example 24, infra.). A compound of Formula 15 in which R.sup.4
is (C.sub.1-4)alkyl can be prepared by reacting a compound of Formula 16
with an (C.sub.2-5)alkanoic acid chloride or anhydride (e.g., acetyl
chloride, propionyl chloride, acetic anhydride, etc.) in the presence of
LDA. The reaction with the acid chloride or anhydride is carried out at
-78.degree. to -15.degree. C., typically at -50.degree. to -78.degree. C.
and preferably at approximately -78.degree. C., and requires 1 to 24 hours
(for further details see Example 25, infra.). The reaction with the
thiocyanic acid is carried out with potassium thiocyanate in the presence
of aqueous acid (e.g., aqueous hydrochloric acid, aqueous sulfuric acid,
aqueous phosphoric acid, etc.) at 50.degree. to 100.degree. C., typically
at 75.degree. to 95.degree. C. and preferably at approximately 85.degree.
C., and requires 1to 5 hours.
Compounds of Formula 16 can be prepared by heating a compound of Formula 17
in n-butyl formate at temperatures of 70.degree. to 105.degree. C.,
preferably at approximately 105.degree. C., for 3 to 24 hours.
Alternatively, compounds of Formula 16 can be prepared by reacting a
compound of Formula 17 with acetic formic anhydride in a suitable solvent
(e.g., methylene chloride, dichloromethane, THF, etc.). The reaction with
acetic formic anhydride is carried out at -15.degree. to 25.degree. C.,
preferably at approximately 0.degree. C., and requires 0.5 to 3 hours.
Compounds of Formula 17 in which R.sup.32 is ethoxycarbonyl can be prepared
by the reductive amination of ethyl glyoxalate with a compound of Formula
3. The reductive amination is carried out in the presence of a chemical
reducing agent (e.g., sodium cyanoborohydride, sodium borohydride, etc.)
or catalytic hydrogenation (e.g., H.sub.2, palladium on carbon; H.sub.2,
nickel; etc.) in a suitable solvent (e.g., methanol, ethanol, ethyl
acetate, any appropriate mixture of suitable solvents, etc.). Optionally
water is removed from the reaction mixture by standard methods (e.g., with
drying agents such as molecular seives or by azeotroping). For further
details of the reaction steps set forth in this and the preceding
paragraph see Example 23, infra.
Compounds of Formula 17 in which R.sup.32 is cyano can be prepared by
reacting a compound of Formula 3 with formaldehyde sodium bisulfite
complex and potassium cyanide in a suitable solvent (e.g., water, aqueous
ethanol, etc.). The reaction is carried out at 50.degree. to 80.degree.
C., typically at 50.degree. to 60.degree. C. and preferably at
approximately 50.degree. C., and requires 0.5 to 2 hours (for further
details see Example 19, infra.).
A method for making compounds of Formula I(a) in which R.sup.3 and R.sup.5
are hydro and R.sup.4 is formyl is depicted by the following Reaction
Scheme VI:
##STR24##
in which each n, t and R.sup.1 are as defined in the Summary of the
Invention with respect to Formula I.
Compounds of Formula I(a) in which R.sup.3 and R.sup.5 are hydro and
R.sup.4 is formyl (Formula 18) are prepared by oxidizing a compound of
Formula 19. The oxidization is effected with an appropriate oxidizing
agent (e.g., lead tetraacetate, periodic acid, etc.) in a suitable solvent
(e.g., acetic acid-benzene, acetic acid-toluene, acetic acid, any
appropriate mixture of suitable solvents, etc.) at 0.degree. to 80.degree.
C., typically at 20.degree. to 40.degree. C. and preferably at
approximately 25.degree. C., and requires 0.25 to 4 hours.
Compounds of Formula 19 are prepared by reacting a compound of Formula 9
with D-(+)-glucosamine. The reaction is carried out in a suitable solvent,
typically an alcohol (e.g., ethanol, methanol, any appropriate mixture of
alcohols, etc.) and preferably ethanol, at 50.degree. to 80.degree. C.,
typically at 70.degree. to 80.degree. C. and preferably at approximately
80.degree. C., and requires 1 to 2 hours. Further details of the reaction
steps set forth in this and the preceding paragraph are provided in
Example 22, infra.
Compounds of Formula I in which R.sup.3 and R.sup.4 are hydro and R.sup.5
is hydroxymethyl can be prepared by reacting a compound of Formula 3, or
the acid addition salt thereof, with thiocyanic acid and dihydroxyacetone
in a suitable solvent (e.g., ethyl acetate, THF, dioxane, any appropriate
mixture of suitable solvents, etc., preferably ethyl acetate) and then
optionally treating the reaction mixture with sulfuric acid (treating with
sulfuric acid enhances purity). The reaction is carried out with potassium
thiocyanate in the presence of acid (e.g., glacial acetic acid, propionic
acid, etc., preferably glacial acetic acid) under nitrogen at 20.degree.
to 50.degree. C. for 0.5 to 3 hours (for further details see Example 18,
infra.).
Compounds of Formula I(b):
A method for making compounds of Formula I(b) in which R.sup.7 is hydro,
aminomethyl, (C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl is depicted
by the following Reaction Scheme VII:
##STR25##
in which R.sup.34 is hydro, aminemethyl, (C.sub.1-4)alkylaminomethyl,
di(C.sub.1-4)alkylaminemethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, or a protected derivative thereof,
and each n, t and R.sup.1 are as defined in the Summary of the Invention
with respect to Formula I.
Compounds of Formula I(b) in which R.sup.7 is hydro, aminemethyl,
(C.sub.1-4)alkylaminemethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl (Formula
20) can be prepared by reacting a compound of Formula 21, or a protected
derivative thereof, with a base (e.g., sodium ethoxide, potassium
t-butoxide, etc.) in a suitable solvent, typically an alcohol (e.g.,
ethanol, t-butanol, isopropanol, any appropriate mixture of suitable
alcohols, etc.) and preferably ethanol, to effect a ring closure and then
removing any protective groups present. The reaction with the base and the
resultant ring closure is carried out at 0.degree. to 75.degree. C.,
preferably approximately 20.degree. C., and requires 1 to 24 hours.
Deprotection can be effected by treating with acid in a suitable solvent
(e.g., 15% anhydrous hydrogen chloride in ethyl acetate, trifluoroacetic
acid in methylene chloride, etc.).
Compounds of Formula 21 are prepared by reacting a compound of Formula 9
with a hydrazide of the formula H.sub.2 NHNC(O)R.sup.34, or a protected
derivative thereof, in a suitable solvent (e.g., DMF, ethyl acetate, any
appropriate mixture of suitable solvents, etc.). The reaction is carried
out at 50.degree. to 100.degree. C., typically at 70.degree. to 90.degree.
C. and preferably at approximately 80.degree. C., and requires 1 to 4
hours.
Hydrazides of the formula H.sub.2 NHNC(O)R.sup.34 can be prepared by
reacting a corresponding methyl aminoacetate, or the protected derivative
thereof, with hydrazine in suitable solvent (e.g., methanol, ethanol, DMF,
any appropriate mixture of suitable solvents, etc.). The reaction is
carried out at 20.degree. to 80.degree. C., typically at 50.degree. to
70.degree. C. and preferably at approximately 65.degree. C., and requires
48 to 96 hours. Suitable methyl aminoacetates are commercially available
or can be easily prepared by methods known in organic synthesis. For
example, the protected derivative of methyl aminoacetate can be prepared
by esterification of N-(tert-butoxycarbonyl)glycine. Other aminoacetates
can be prepared by reacting a corresponding methyl chloroacetate with an
amine of the formula NHR.sup.36 R.sup.37 (in which R.sup.36 and R.sup.37
are independently (C.sub.1-4)alkyl or together are --(CH.sub.2).sub.4 --,
--(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 -- or
--(CH.sub.2).sub.2 NR.sup.38 (CH.sub.2).sub.2 --, wherein R.sup.38 is
hydro or (C.sub.1-4)alkyl) in a suitable solvent (e.g., acetonitrile,
ethanol, DMF, any appropriate mixture of suitable solvents, etc.). The
reaction is carried out at 0.degree. to 100.degree. C., typically at
65.degree. to 95.degree. C. and preferably at approximately 80.degree. C.,
and requires 1 to 48 hours. Further details of the reaction steps set
forth in this and the two preceding paragraphs are provided in Example 26.
Compounds of Formula I(c):
A method for making compounds of Formula I(c) in which R.sup.7 is hydro is
depicted by the following Reaction Scheme VIII:
##STR26##
in which each n, t, and R.sup.1 are as defined in the Summary of the
Invention with respect to Formula I.
Compounds of Formula I(c) in which R.sup.7 is hydro (Formula 22) can be
prepared by reacting a compound of Formula 23 with a suitable base (e.g.,
10% sodium hydroxide, potassium t-butoxide, etc.). The reaction with the
base and resultant ring closure is carried out at 20.degree. to
100.degree. C., typically at 50.degree. to 90.degree. C. and preferably at
approximately 70.degree. C., and requires 1 to 24 hours.
Compounds of Formula 23 are prepared by reacting a compound of Formula 24
with an isothiocyanate (e.g., trimethylsilyl isothiocyanate, etc.) in a
suitable solvent (e.g., toluene, 1,2-dimethoxyethane, any appropriate
mixture of suitable solvents, etc.). The reaction is carried out at
20.degree. to 110.degree. C., typically at 50.degree. to 90.degree. C. and
preferably at approximately 70.degree. C., and requires 18 to 24 hours.
Compounds of Formula 24 are prepared by reacting a compound of Formula 7
with formic hydrazide in a suitable solvent (e.g., ethanol, isopropanol,
etc.) and then reducing. The reaction with the hydrazide is carried out in
the presence of acid (e.g., hydrochloric acid, p-toluene sulfonic acid,
boric acid, trifluoroacetic acid, etc.) at 20.degree. to 100.degree. C.,
typically at 60.degree. to 90.degree. C. and preferably at approximately
75.degree. C., and requires 1 to 5 hours. The reduction can be effected
with a chemical reducing agent (e.g., lithium borohydride, sodium
borohydride, sodium cyanoborohydride, etc.) in a suitable solvent,
typically an alcohol (e.g., ethanol, any appropriate mixture of alcohol
etc.), preferably ethanol at 20.degree. to 80.degree. C. and requires 8 to
24 hours. Further details of the reaction steps set forth in this and the
preceding paragraph are provided in Example 27, infra.
Compounds of Formula I(c) in which R.sup.7 is amino can be prepared by
reacting a compound of Formula 5 with 1,2,4-triazol-4-ylamino to give the
corresponding 4-aminotriazolium salt and then sulfurizing. The reaction
with the 4-amino›1,2,4!triazole is carried out at 50.degree. to
100.degree. C., typically at 80.degree. to 90.degree. C. and preferably at
approximately 90.degree. C., and requires 1 to 8 hours. The sulfurization
is carried out with lac sulfur in the presence of a mild base (e.g.,
triethylamine, etc.) at 50.degree. to 125.degree. C., typically at
80.degree. to 100.degree. C. and preferably at approximately 90.degree.
C., and requires 1 to 8 hours (for further details see Example 28,
infra.).
Additional Processes for Making Compounds of Formula I:
Compounds of Formula I in which R.sup.5 is 1H-tetrazol-5-yl can be prepared
by reacting a compound of Formula I in which R.sup.5 is cyano with a
hydrazoic acid derivative (e.g., tributyltin azide, triphenylsilyl azide,
t-butyldiphenylsilyl azide, etc.). The reaction is carried out at
100.degree. to 150.degree. C., typically at 120.degree. to 140.degree. C.
and preferably at approximately 130.degree. C., and requires 2 to 18 hours
(for further details see Example 21, infra.).
Compounds of Formula I in which R.sup.5 is carbamoyl can be prepared by
hydrolyzing compound of Formula I in which R.sup.5 is cyano. The
hydrolysis can be carried out with aqueous hydrochloric acid at
100.degree. to 140.degree. C., typically at 125.degree. to 135.degree. C.
and preferably at approximately 130.degree. C., and requires 2 to 18
hours. Proceeding as described above,
5,6-difluoroindan-2-yl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl-carboxamide,
m.p.>280.degree. C., was prepared.
Compounds of Formula I in which R.sup.5 is --C(NH)NR.sup.15 R.sup.16 can be
prepared by reacting a compound of Formula I in which R.sup.5 is cyano
with a reagent of the formula (CH.sub.3).sub.2 AlNR.sup.15 R.sup.16, in a
suitable solvent (e.g., toluene, benzene, methylene chloride,
tetrachloroethane, any appropriate mixture of suitable solvents, etc.).
The reaction is carried out at 20.degree. to 130.degree. C., typically at
60.degree. to 100.degree. C. and preferably at approximately 80.degree.
C., and requires 1 to 18 hours. The reagent of the formula
(CH.sub.3).sub.2 AlNR.sup.15 R.sup.16 is prepared by reacting an amine of
the formula NHR.sup.15 R.sup.16 with trimethylaluminum. Proceeding as
described above
5-(aminoiminomethyl)-1-(5,6-difluoroindanyl-2-yl)-1,3-dihydroimidazole-2-t
hione and
1-(5,6-difluoroiindan-2-yl)-5-›imino-(2,2,2-trifluoroethylamino)methyl!-1,
3-dihydroimidazole-2-thione, m.p. 199.degree.-200.degree. C., were
prepared.
Compounds of Formula I in which R.sup.5 is 4,5-dihydroimidazol-2-yl can be
prepared by reacting compound of Formula I in which R.sup.5 is cyano with
ethylenediamine. The reaction can be carried out by heating the reactants
in the presence p-toluenesulfonic acid at 100.degree. to 250.degree. C.,
typically at 180.degree. to 220.degree. C. and preferably at approximately
200.degree. C., for 1 to 3 hours. Proceeding as described above,
1,2,3,4-tetrahydronaphthalen-2-yl-5-(4,5-dihydroimidazol-2-yl)-1,3-dihydro
imidazole-2-thione, m.p. 130.degree.-145.degree. C., was prepared.
Compounds of Formula I in which R.sup.3 and R.sup.4 are hydro and R.sup.5
is aminomethyl can be prepared by reducing compound of Formula I in which
R.sup.5 is cyano. The reduction can be effected with a chemical reducing
agent (e.g., lithium aluminum hydride, borane in THF, aluminum hydride,
etc.) in a suitable solvent (e.g., THF, 1,2-dimethoxyethane,
2,2-dimethoxyethyl ether, any appropriate mixture of suitable solvents,
etc.) at 0.degree. to 65.degree. C., typically at 0.degree. to 20.degree.
C. and preferably at approximately 0.degree. C. and requires 1 to 5 hours
(for further details see Example 20, infra.).
A preferred method for making compounds of Formula 1 in which R.sup.3 and
R.sup.4 are hydro and R.sup.5 is aminomethyl is depicted by the following
Reaction Scheme IX:
##STR27##
in which R.sup.35 is hydro, (C.sub.1-4)alkyl or trifluoro(C.sub.1-4)alkyl
and each n, t and R.sup.1 are as defined in the Summary of the Invention
with respect to Formula I.
The acid addition salt of a compound of Formula I in which R.sup.3 and
R.sup.4 are each hydro and R.sup.5 is aminomethyl (Formula 25) can be
prepared by acid catalyzed hydrolysis of the corresponding compound of
Formula I in which R.sup.5 is formylaminomethyl,
(C.sub.1-4)alkylcarbonylaminomethyl or
trifluoro(C.sub.1-4)alkylcarbonylaminomethyl (Formula 26). The hydrolysis
is carried out in a suitable solvent, typically an alcohol (e.g.,
isopropanol, ethanol, methanol, any appropriate mixture of alcohols, etc.)
and preferably isopropanol, and under nitrogen at 65.degree. to 82.degree.
C., preferably at reflux, and requires 0.5 to 4 hours.
Pharmaceutically acceptable acid addition salts of compounds of Formula I
in which R.sup.3 and R.sup.4 are each hydro and R.sup.5 is aminomethyl can
be prepared by performing the hydrolysis with a pharmaceutically
acceptable acid (e.g., 2 to 8 equivalents of concentrated hydrochloric
acid, preferably approximately 5 equivalents). Alternatively, any acid
addition salt form of a compound of Formula 25 can be converted to the
corresponding free base form by reacting with an acceptable inorganic or
organic base and then converted to a pharmaceutically acceptable acid
addition salt by reacting with an appropriate pharmaceutically acceptable
acid. Further details of the reaction steps set forth in this paragraph
and the preceding paragraph are provided in Example 31, infra.
Compounds of Formula I in which R.sup.5 is formylaminomethyl,
(C.sub.1-4)alkylcarbonylaminomethyl or
trifluoro(C.sub.1-4)alkylcarbonylaminomethyl can be prepared by reacting
the corresponding compound of Formula I in which R.sup.5 is hydroxymethyl
(Formula 27) with a primary amide of the formula H.sub.2 NC(0)R.sup.35
(e.g., formamide, acetamide, trifluoroacetamide, etc.). The reaction is
carried out by adding the confound of Formula 27 to the amide and then
heating the mixture under a stream of nitrogen for 0.5 to 2 hours at
150.degree. to 190.degree. C. Preferably the amide is formamide and the
reaction is carried out by heating at 170.degree. to 175.degree. for
approximately 1 hour. Proceeding similarly but substituting urea for the
primary amide, compounds of Formula I in which R.sup.5 is ureidomethyl can
be prepared. Further details of the reaction steps set forth in this
paragraph are provided in Example 29, infra.
A preferred process for preparing compounds of Formula 26 comprises
reacting a compound of Formula 27 with an ammonium salt of the formula
NH.sub.4.sup.+- OC(0)R.sup.35 (e.g., ammonium formate, ammonium acetate,
ammonium trifluoroacetate, etc., preferably ammonium formate). For
example, a compound of Formula 27 can be reacted with ammonium formate to
give a compound of Formula 24 wherein R.sup.35 is hydro. The reaction is
carried out neat or in formamide, preferably formamide at 100.degree. to
180.degree. C., preferably at 120.degree. to 150.degree. C., and requires
1 to 2 hours (for further details see Example 30, infra.).
Compounds of Formula I in which R.sup.3 and R.sup.4 are hydro and R.sup.5
is aminomethyl, (C.sub.1-4)alkylaminomethyl,
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl can be prepared by converting a
compound of Formula I in which R.sup.5 is hydroxymethyl to a compound of
Formula 28:
##STR28##
in which L is a leaving group and n, t and R.sup.1 are as defined in the
Summary of the Invention with respect to Formula I, and reacting the
compound of Formula 28 with an amine of the formula HNR.sup.36 R.sup.37,
in which R.sup.36 and R.sup.37 are independently (C.sub.1-4)alkyl or
together are --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --,
--(CH.sub.2).sub.2 O (CH.sub.2).sub.2 -- or --(CH.sub.2).sub.2 NR.sup.38
(CH.sub.2).sub.2 -- (in which R.sup.38 is hydro or (C.sub.1-4)alkyl). The
conversion to the compound of Formula 28 is effected with an appropriate
agent for forming a suitable leaving group (e.g., methanesulfonyl
chloride, thionyl chloride, phosphorous pentachloride, phosphorous
oxychloride, etc.) in a suitable solvent (e.g., methylene chloride,
chloroform, THF, any appropriate mixture of suitable solvents, etc.). The
reaction with the amine is carried out in a suitable solvent (e.g., THF,
1,2-dimethoxyethane, acetonitrile, any appropriate mixture of suitable
solvents, etc.) at -10.degree. to 20.degree. C. and requires 1 to 4 hours.
Further details of the reaction steps set forth in this paragraph are
provide in Example 32, infra.
Compounds of Formula I in which R.sup.4 is aminomethyl can be prepared by
reacting a corresponding compound of Formula I in which R.sup.4 is formyl
with hydroxylamine hydrochloride to give the corresponding oxime and then
reducing. The reaction with the hydroxylamine hydrochloride is carried out
in the presence of a suitable base (e.g., sodium hydroxide, sodium
acetate, etc.) and in a suitable solvent, typically an alcohol (e.g.,
ethanol, methanol, any appropriate mixture of alcohols, etc.) or a mixture
of alcohol and water (e.g., ethanol/water (1:1), etc.) at 20.degree. to
100.degree. C., typically at 50.degree. to 70.degree. C. and preferably at
approximately 60.degree. C., and requires 1 to 8 hours. The reduction of
the oxime can be effected with a chemical reducing agent (e.g., lithium
aluminum hydride, etc.) in a suitable solvent (e.g., THF, any mixture of
suitable solvents, etc.) at -50.degree. to 50.degree. C., typically at
-20.degree. to 20.degree. C. and preferably at approximately 0.degree. C.
For further details of the reaction steps set forth in this paragraph see
Example 47, infra.
Compounds of Formula I in which R.sup.4 is --CH.sub.2 NHR.sup.10, wherein
R.sup.10 is as defined in the Summary of the Invention with respect to
Formula I, can be prepared by reductive amination of a compound of Formula
I in which R.sup.4 is formyl with an amine of the formula NH.sub.2
R.sup.10 (e.g., glycine tert-butyl ester hydrochloride, glycinamide
hydrochloride, phenethylamine, methyl 4-(2-amino-ethyl)benzoate, etc.).
The reductive amination is carried out in the presence of a chemical
reducing agent (e.g., sodium cyanoborohydride, sodium borohydrids, etc.)
or catalytic hydrogenation (e.g., H.sub.2, palladium on carbon, H.sub.2,
Raney.RTM. nickel, etc.) in a suitable solvent (e.g., THF, water, ethyl
acetate, alcohol, any appropriate mixture of solvents, etc.), typically an
alcohol (e.g., ethanol, methanol, any appropriate mixture of alcohols,
etc.) at 20.degree. to 100.degree. C., preferably at approximately
50.degree. C., and requires 1 to 8 hours (for further details see Example
48, infra.).
Compounds of Formula I in which R.sup.4 is 1-hydroxy(C.sub.1-4)alkyl can be
prepared by reacting a corresponding compound of Formula I in which
R.sup.4 is formyl with an appropriate alkylating agent (e.g.,
methylmagnesium chloride, ethylmagnesium chloride, n-propylmagnesium
chloride, etc.). The alkylation is carried out neat at -20.degree. to
60.degree. C., typically at 0.degree. to 25.degree. C. and preferably at
approximately 0.degree. C. (for further details see Example 40, infra.).
Compounds of Formula I in which R.sup.3, R.sup.5 or R.sup.8 is
--NHC(NR.sup.11)NHR.sup.12 or compounds of Formula I in which R.sup.4,
R.sup.5 or R.sup.7 is --CH.sub.2 C(NR.sup.11)NHR.sup.12 in which R.sup.11
is hydro, acetyl or tert-butoxycarbonyl and R.sup.12 is acetyl or
tert-butoxycarbonyl can be prepared by reacting a compound of Formula I in
which R.sup.3, R.sup.4, R.sup.5, R.sup.7 or R.sup.8 is amino or
aminomethyl with an appropriately substituted amidine (e.g., N.sup.1
-(tert-butoxy-carbonyl)methylthioamidine, N.sup.1,N.sup.2
-di(tert-butoxycarbonyl)methylthioamidine, N.sup.1,N.sup.2
-di(acetyl)methylthioamidine, etc.). The reaction is carried out in a
suitable solvent (e.g., THF, methanol, ethanol, DMF, water, any
appropriate mixture of suitable solvents, etc., preferably THF) at
0.degree. C. to reflux, typically at 20.degree. C. to reflux and
preferably at approximately 50.degree. C., under an inert atmosphere, and
requires 1 to 24 hours (for further details see Example 49, infra.).
Compounds of Formula I in which R.sup.3, R.sup.5 or R.sup.8 is
--NHC(NR.sup.11)NHR.sup.12 or compounds of Formula I in which R.sup.4,
R.sup.5 or R.sup.7 is --CH.sub.2 NHC(NR.sup.11)NHR.sup.12, wherein
R.sup.11 and R.sup.12 are hydro, can be prepared by treating the
corresponding compound of Formula I wherein R.sup.11 and/or R.sup.12 are
acetyl or tert-butoxycarbonyl with a suitable acid (e.g., trifluoroacetic
acid (TFA), hydrochloric acid, hydrobromic acid, sulfuric acid, etc.,
preferably TFA) and optionally with a suitable cosolvent (e.g., ethanol).
The acid treatment is carried out at 0.degree. to 120.degree. C.,
typically at 0.degree. to 80.degree. C. and preferably at approximately
25.degree. C., and requires 0.5 to 12 hours (for further details see
Example 50, infra.).
Compounds of Formula I in which R.sup.3 and R.sup.5 are hydro and R.sup.4
is di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl can be prepared by alkylating a compound of Formula I
in which R.sup.3, R.sup.4 and R.sup.5 are each hydro with an appropriately
N,N-disubstituted methyleneammonium salt. The alkylation is carried out in
a suitable solvent (e.g., DMF, acetonitrile, any appropriate mixture of
suitable solvents, etc., preferably DMF) at 50.degree. to 130.degree. C.,
typically at 80.degree. to 110.degree. C. and preferably at approximately
95.degree. C., and requires 1 to 24 hours.
Compounds of Formula I in which R.sup.4 is hydro, R.sup.5 is
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl and R.sup.3 is other than hydro can be prepared by
alkylating a corresponding compound of Formula I in which R.sup.5 is hydro
with about 1 molar equivalent of an appropriately N,N-disubstituted
methyleneammonium salt. The alkylation is carried out in a suitable
solvent (e.g., DMF, DMPU, acetonitrile, any appropriate mixture of
suitable solvents, etc., preferably DMF) at 0.degree. C. to reflux,
typically at 25.degree. to 100.degree. C. and preferably at approximately
80.degree. C., and requires 1 to 24 hours (for further details see Example
35, infra.).
Compounds of Formula I in which R.sup.3 and R.sup.4 are hydro and R.sup.5
is di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl can be prepared by alkylating a thio protected
derivative of a corresponding compound of Formula I in which R.sup.5 is
hydro (e.g., the 3-(imidazol-2-ylthio)propionate derivative thereof) with
about 1 molar equivalent of an appropriately N,N-disubstituted
methyleneammonium salt and then deprotecting. The alkylation is carried
out in a suitable solvent (e.g., DMF, DMPU, acetonitrile, any appropriate
mixture of suitable solvents, etc., preferably DMF) at 50.degree. to
130.degree. C., preferably at 80.degree. to 100.degree. C., and requires 1
to 24 hours. The deprotection can be effected with a suitable base (e.g.,
a sodium alkoxide such as sodium ethoxide and the like, sodium hydroxide,
potassium hydroxide, etc. preferably sodium ethoxide) at 0.degree. to
50.degree. C., preferably at approximately 25.degree. C.
A suitable thio protected derivative can be prepared by reacting a compound
of Formula I in which R.sup.3 is hydro with ethyl acrylate to give a
3-(imidazol-2-ylthio)propionate derivative. The protection step is carried
out in the presence of an acid (e.g., anhydrous hydrochloric acid) in a
suitable solvent typically an alcohol (e.g., methanol, ethanol, any
appropriate mixture of suitable alcohols, etc.) and preferably ethanol, at
0.degree. C. to reflux, typically at 50.degree. C. to reflux and
preferably at approximately 80.degree. C.
Compounds of Formula I in which R.sup.3 is hydro and R.sup.4 and R.sup.5
are each di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl can be prepared by alkylating a protected derivative
of a corresponding compound of Formula I in which R.sup.4 and R.sup.5 are
each hydro with 2 to 15 molar equivalents of an appropriately
N,N-disubstituted methyleneammonium salt, typically 5 to 10 molar
equivalents and preferably approximately 7 molar equivalents, and then
deprotecting. The alkylation is carried out in a suitable solvent (e.g.,
DMF, DMPU, acetonitrile, any appropriate mixture of suitable solvents,
etc., preferably DMF) at 50.degree. to 130.degree. C., typically at
90.degree. to 110.degree. C. and preferably at approximately 100.degree.
C., and requires 1 to 24 hours (for further details see Example 36,
infra.).
Compounds of Formula I in which R.sup.4 and/or R.sup.5 are hydroxymethyl
can be prepared by reducing a compound of Formula I in which R.sup.4
and/or R.sup.5 is ethoxycarbonyl. The reduction can be effected with a
chemical reducing agent (e.g., sodium borohydride, calcium borohydride,
lithium borohydride, lithium aluminum hydride, etc., preferably sodium
borohydride in the presence of calcium chloride) in a suitable solvent
(e.g., THF, diglyme, dioxane, any appropriate mixture of suitable
solvents, etc., preferably THF) at -20.degree. C. to reflux, typically at
0.degree. to 80.degree. C. and preferably at approximately 50.degree. C.,
requiring 1 to 72 hours (for further details see Example 33, infra.).
Compounds of Formula I in which R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, or R.sup.8 is a group selected from aroyl, heteroaroyl,
aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which aroyl,
heteroaroyl, aryl and heteroaryl are further substituted by a
1H-tetrazol-5-yl substituent can be prepared by reacting a corresponding
of Formula I in which the aroyl, heteroaroyl, aryl and heteroaryl
substituent which are further substituted by a cyano substituent with a
hydrazoic acid derivative (e.g., tributyltin azide). The reaction is
carried out neat or in a suitable solvent (e.g., xylene, toluene, benzene,
any appropriate mixture of suitable solvents, etc., preferably xylene) at
80.degree. to 150.degree. C., typically at 80.degree. to 130.degree. C.
and preferably at reflux, and requires 4 to 24 hours (for further details
see Example 39, infra.).
Compounds of Formula I in which R.sup.5 or both R.sup.4 and R.sup.5 are
1H-tetrazol-5-ylaminocarbamoyl, 2-(dimethylamino)ethylcarbamoyl,
4-methylpiperazin-1-ylcarbonyl, methylsulfonylanilinocarbonyl or
2-(dimethylamino)ethylmercaptocarbonyl can be prepared by reacting a
compound of Formula I in which R.sup.5 or both R.sup.4 and R.sup.5 are
carboxy, or an acid derivative thereof, with an appropriate amine or thiol
(i.e., 5-amino-1H-tetrazole, 2-(dimethylamino)ethylamine,
4-methylpiperizine, 4-methylsulfonylaminoaniline or
2-dimethylaminoethanethiol hydrochloride). For example, compounds of
Formula I in which R.sup.5 is 1H-tetrazol-5-ylcarbamoyl can be prepared by
converting the corresponding carboxylic acid to an acid halide and then
reacting the acid halide with 5-amino-1H-tetrazole. The reaction with the
5-amino-1H-tetrazole is carried out in a suitable solvent (e.g., pyridine,
DMF, any appropriate mixture of suitable solvents, etc.) at 0.degree. to
40.degree. C., typically at 20.degree. to 30.degree. C. and preferably at
approximately 25.degree. C., and requires 1 to 24 hours (for further
details see Example 41, infra.).
Compounds of Formula I in which R.sup.5 is 2-(dimethylamino)ethylcarbamoyl,
4-methylpiperazin-1-ylcarbonyl or 2-(dimethylamino)ethylmercaptocarbonyl
can be prepared by treating a corresponding carboxylic acid with a
coupling agent (e.g., 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide,
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP),
etc.) in a suitable solvent (e.g., THF, methylene chloride, DMF, any
appropriate mixture of suitable solvent, etc.) and then reacting with the
appropriate amine or thiol. The reaction with the amine or thiol is
carried out at 0.degree. to 80.degree. C., typically at 20.degree. to
30.degree. C. and preferably at approximately 25.degree. C., and requires
1 to 24 hours (for further details see Example 42, infra.).
Compounds of Formula I in which R.sup.3, R.sup.6 or R.sup.8 is
2-(C.sub.1-4)alkyloxycarbonylethyl can be prepared by reacting a compound
of Formula I in which R.sup.3, R.sup.6 or R.sup.8, respectively, is hydro
with (C.sub.1-4)alkyl acrylate (e.g., methyl acrylate, ethyl acrylate,
etc.). The reaction is carried out in the presence of base (e.g., sodium
ethoxide, benzyltrimethylammoniumhydroxide, sodium hydride, etc.) and in a
suitable solvent (e.g., ethanol, N,N-dimethylformamide,
N,N-dimethylacetamide, acetonitrile, etc.) at 50.degree. to 100.degree.
C., preferably approximately at 80.degree. C., and requires 1 to 6 hours
(for further details see Example 34, infra.).
Compounds of Formula I in which a R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 substituent is carboxy or a group which is further
substituted by a carboxy substituent can be prepared by hydrolysis of a
corresponding compound of Formula I in which a R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 or R.sup.8 substituent is (C.sub.1-4)alkyloxycarbonyl or
a group which is further substituted by a (C.sub.1-4)alkyloxycarbonyl
substituent. The hydrolysis can be carried out with an aqueous base (e.g.,
potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) in a
suitable solvent, typically an alcohol (e.g., ethanol, methanol,
isopropanol, any appropriate mixture of alcohols, etc.) and preferably
ethanol, or an aqueous acid (e.g., hydrochloric acid, trifluoroacetic
acid, sulfuric acid, hydrochloric acid, hydrobromic acid, etc.) in a
suitable solvent (e.g., methylene chloride, ethyl acetate, dioxane, DMF,
THF, etc.) at 20.degree. to 120.degree. C., typically at 90.degree. to
110.degree. C. and preferably at approximately 100.degree. C., and
requires 4 to 24 hours (for further details see Example 37, infra.).
Compounds of Formula I in which a R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 is carbamoyl or a group which is further substituted by
a carbamoyl substituent can be prepared by amination of a corresponding
compound of Formula I in which a R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 is carboxy or a group which is further substituent by a
carboxy substituent. The amination can be carried out by converting the
carboxylic acid to the corresponding acid chloride and then reacting the
acid chloride with aqueous ammonium hydroxide. Converting the acid to the
acid chloride is carried out with an appropriate chlorinating agent (e.g.,
thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.) and in
a suitable solvent (e.g., DMF, methylene chloride, dichloroethane, any
appropriate mixture of suitable solvents, etc., preferably DMF) at
10.degree. to 40.degree. C., typically at 15.degree. to 30.degree. C. and
preferably at approximately 20.degree. C., and requires 2 to 18 hours. The
reaction between the acid chloride and the aqueous ammonium hydroxide is
carried out at 0.degree. to 50.degree. C., typically at 20.degree. to
30.degree. C. and preferably at approximately 25.degree. C., and requires
0.5 to 24 hours. Further details of the reaction steps set forth in this
paragraph are provided in Example 38, infra.
Compounds of Formula I in which R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7
or R.sup.8 is (C.sub.1-4)alkyloxycarbonyl or a group that is further
substituted by a (C.sub.1-4)alkyloxycarbonyl group can be prepared by
reacting a compound of Formula I in which R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 or R.sup.8 is carboxy or a group which is further
substituted by a carboxy group with a (C.sub.1-4)alcohol. The reaction is
carried out at 20.degree. to 110.degree. C., preferably approximately
85.degree. C., and requires 8 to 72 hours.
Compounds of Formula I in which R.sup.10 is (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, aroyl or heteroaroyl can be
prepared by reacting a corresponding compound of Formula I in which
R.sup.3, R.sup.4, R.sup.5, R.sup.7 or R.sup.8 is amino or aminomethyl with
an appropriate acylating agent (e.g., acyl halides such as
dimethylcarbamyl chloride, benzoyl chloride, nicotinoyl chloride and the
like, anhydrides such as acetic anhydride and the like, activated esters
such as methyl chloroformate and the like, etc.) or a protected derivative
thereof. The reaction is carried out in a suitable solvent (e.g.,
methylene chloride, THF, pyridine, water, any appropriate mixture of
suitable solvents, etc., preferably pyridine) at -10.degree. to 40.degree.
C., typically at 15.degree. to 35.degree. C. and preferably at
approximately 25.degree. C., and requires 0.5 to 8 hours (for further
details see Example 44, infra.).
Alternatively, compounds of Formula I in which R.sup.10 is carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, aroyl or heteroaroyl can be
prepared by reacting a corresponding compound of Formula I in which
R.sup.3, R.sup.4, R.sup.5, R.sup.7 or R.sup.8 is amino or aminomethyl with
an appropriate acid (e.g., picolinic acid and the like) or a protected
derivative thereof (e.g., N-(tert-butoxycarbonyl)glycine and the like).
The reaction is carried out in the presence of a non-nucleophilic base
(e.g., N,N-diisopropylethylamine (DIEA), N,N-dicyclohexylmethylamine,
etc., preferably DIEA) and a suitable coupling agent (e.g., PyBOP,
1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide, etc., preferably
PyBOP) in a suitable solvent (e.g., DMF, DMPU, acetonitrile, THF,
methylene chloride, any appropriate mixture of suitable solvents, etc.,
preferably DMF) at -20.degree. to 80.degree. C., typically at 0.degree. to
30.degree. C. and preferably at approximately 25.degree. C. (for further
details see Example 45, infra.).
Alternatively, compounds of Formula I in which R.sup.3, R.sup.5 or R.sup.8
is --NHR.sup.10 or compounds of Formula I in which R.sup.4, R.sup.5 or
R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkylcarbamoyl, can be prepared by reacting a corresponding
compound of Formula I in which R.sup.3, R.sup.4, R.sup.5, R.sup.7 or
R.sup.8 is amino or aminomethyl with (C.sub.1-4)alkyl isocyanate. The
reaction is carried out optionally in the presence of a base (e.g.,
triethylamine, pyridine, etc.) in a suitable solvent (e.g., THF, benzene,
methylene chloride, any appropriate mixture of suitable solvents, etc.,
preferably THF) at 0.degree. C. to reflux, typically at 25.degree. to
80.degree. C. and preferably at approximately 50.degree. C. (for further
details see Example 46, infra.).
Compounds of Formula I in which R.sup.1 is hydroxy and/or R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two hydroxy substituents) can be prepared by de-methylating a compound
of Formula I in which R.sup.1 is methoxy and/or in which R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is a group selected from aroyl,
heteroaroyl, aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which
aroyl, heteroaroyl, aryl and heteroaryl are further substituted with one
to two methoxy substituents). The de-methylation can be carried out with
boron tribromide in suitable solvent (e.g., methylene chloride,
1,2-dichloroethane, nitromethane, any appropriate mixture of suitable
solvents, etc., preferably methylene chloride) at -10.degree. to
20.degree. C., typically at -5.degree. to 5.degree. C. and preferably at
approximately 0.degree. C., requiring 0.5 to 4 hours. For further details
of the reactions step set forth in this paragraph see Example 43, infra.
Compounds of Formula I can be prepared as their individual stereoisomers by
reacting a racemic mixture thereof with an optically active resolving
agent to form a pair of diastereomeric compounds, separating the
diastereomers and recovering the optically pure enantiomer. While
resolution of enantiomers can be carried out using covalent diastereomeric
derivatives of compounds of Formula I, dissociable complexes are preferred
(e.g., crystalline diastereoisomeric salts). In that compounds of Formula
I contain a basic amine group, such crystalline diastereoisomeric salts
can be prepared by using a suitable optically active acid as the resolving
agent (e.g., tartaric acid, mandelic acid, malic acid, the 2-arylpropionic
acids in general, camphorsulfonic acid, etc.).
Diastereomers have distinct physical properties (e.g., melting points,
boiling points, solubilities, reactivity, etc.) and can be readily
separated by taking advantage of these dissimilarities. The diastereomers
can be separated by chromatography or, preferably, by
separation/resolution techniques based upon differences in solubility. The
optically pure enantiomer is then recovered, along with the resolving
agent, by any practical means that would not result in racemization. A
more detailed description of the techniques applicable to the resolution
of stereoisomers of compounds from their racemic mixtures can be found in
Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and
Resolutions, John Wiley & Sons, Inc. (1981).
In summary, an aspect of this invention is a process for the preparation of
a compound of Formula I:
##STR29##
in which: n is 0, 1 or 2;
t is 0, 1, 2 or 3;
R.sup.1 is independently halo, hydroxy or (C.sub.1-4)alkyloxy; and
R.sup.2 is attached at the .alpha.-, .beta.- or .gamma.-position and is a
group selected from Formulae (a), (b) and (c):
##STR30##
in which: R.sup.4 is hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9
{in which q is 0, 1, 2, 3 or 4 and R.sup.9 is carboxy,
(C.sub.1-4)alkyloxycarbonyl, carbamoyl or a group selected from aryl and
heteroaryl (which group is optionally further substituted with one to two
substituents independently selected from hydroxy, (C.sub.1-4)alkyloxy,
cyano, 1H-tetrazo-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl)} and
R.sup.5 is hydro or --NHR.sup.10 {in which R.sup.10 is hydro,
(C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino (C.sub.1-4)alkanoyl, di(C.sub.1-4)alkylamino
(C.sub.1-4)alkanoyl, a group selected from aroyl and heteroaroyl (which
aroyl and heteroaroyl are optionally further substituted with one to two
substituents independently selected from hydroxy, (C.sub.1-4)alkyloxy,
cyano, 1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11)NHR.sup.12 (in which R.sup.11 and R.sup.12 are independently
hydro, acetyl or tert-butoxycarbonyl)}; or R.sup.4 and R.sup.5 are each
hydro and R.sup.3 is --NHR.sup.10 (in which R.sup.10 is as defined above);
or R.sup.5 is hydro, R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in
which q and R.sup.9 are as defined above) and R.sup.4 is (C.sub.1-4)alkyl,
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
formyl, 1-hydroxy(C.sub.1-4)alkyl or --CH.sub.2 NHR.sup.13 {in which
R.sup.13 is hydro, (C.sub.1-4)alkyl, (C.sub.1-4)alkanoyl,
trifluoro(C.sub.1-4)alkanoyl, carbamoyl, (C.sub.1-4)alkyloxycarbonyl,
(C.sub.1-4)alkylcarbamoyl, di(C.sub.1-4)alkylcarbamoyl,
amino(C.sub.1-4)alkanoyl, (C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl, carboxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkyloxycarbonyl(C.sub.1-4)alkyl, carbamoyl(C.sub.1-4)alkyl, a
group selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are optionally further substituted with one to two substituents
independently selected from hydroxy, (C.sub.1-4)alkyloxy, cyano,
1H-tetrazol-5-yl, carboxy and (C.sub.1-4)alkyloxycarbonyl) or
--C(NR.sup.11)NHR.sup.12 (in which R.sup.11 and R.sup.12 are as defined
above)}; or R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and
R.sup.9 are as defined above), R.sup.4 is hydro, (C.sub.1-4)alkyl or
--C(O)R.sup.14 (in which R.sup.14 is amino, hydroxy (C.sub.1-4)alkyloxy,
2-(dimethylamino)ethylamino, 4-methylpiperazin-1-yl,
2-(dimethylamino)ethylmercapto, 4-(methylsulfonylamino)anilino or
1H-tetrazol-5-ylamino) and R.sup.5 is cyano, hydroxymethyl,
1H-tetrazol-5-yl, 4,5- dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl,
piperidin -1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl, --C(O)R.sup.14 (in which R.sup.14
are as defined above), --C(NH)NR.sup.15 R.sup.16 (in which R.sup.15 and
R.sup.16 independently hydro, (C.sub.1-4)alkyl or
trifluoro(C.sub.1-4)alkyl) or --CH.sub.2 NR.sup.10 R.sup.17 (in which
R.sup.10 is as defined above and R.sup.17 is hydro or C.sub.1-4)alkyl); or
R.sup.3 is hydro or --(CH.sub.2).sub.q R.sup.9 (in which q and R.sup.9 are
as defined above) and R.sup.4 and R.sup.5 are dependently
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl
or hydroxymethyl;
R.sup.6 is hydro, 2-carboxyethyl, 2-carbamoylethyl or
2-(C.sub.1-4)alkyloxycarbonylethyl;
R.sup.7 is hydro, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl,
morpholin-4-ylmethyl, piperazin-1-ylmethyl,
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl or --CH.sub.2 NR.sup.10 R.sup.17
(in which R.sup.10 and R.sup.17 are as defined above); and
R.sup.8 is hydro, 2-carboxyethyl, 2-carbamoylethyl,
2-(C.sub.1-4)alkyloxycarbonylethyl or --NHR.sup.10 (in which R.sup.10 are
as defined above); and the pharmaceutically acceptable salts, individual
isomers, and mixtures of isomers thereof; which process comprises:
(a) reacting a compound of Formula 3:
##STR31##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with a dialkyloxyacetaldehyde in the presence of a chemical
reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.2 is a
group of Formula (a) wherein R.sup.3, R.sup.4 and R.sup.5 are each hydro;
or
(b) reacting a compound of Formula 5:
##STR32##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with 1,2,4-triazol-4-ylamino and then sulfurizing to give a
compound of Formula I in which R.sup.2 is a group of Formula (c) wherein
R.sup.8 is amino; or
(c) reacting a compound of Formula 7:
##STR33##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with with a 2,2-dialkyloxyethylamine in the presence of a
chemical reducing agent or catalytic hydrogenation and then treating with
thiocyanic acid to give a compound of Formula I in which R.sup.2 is a
group of Formula (a) wherein R.sup.3, R.sup.4 and R.sup.5 are each hydro;
(d) reacting a compound of Formula 9:
##STR34##
in which each n, t and R.sup.1 are as defined above with respect to
Formula I with a 2,2-dialkyloxyethylamine and then treating with acid to
give a compound of Formula I in which R.sup.2 is a group of Formula (a)
wherein R.sup.3, R.sup.4 and R.sup.5 are each hydro; or
(e) reacting a compound of Formula 9 with aminoacetonitrile hydrochloride
and then treating with base to give a compound of Formula I in which
R.sup.2 is a group of Formula (a) wherein R.sup.3 and R.sup.4 are each
hydro and R.sup.5 is amino; or
(f) reacting a compound of Formula 9 with D-(+)-glucosamine and then
oxidizing to give a compound of Formula I in which R.sup.2 is a group of
Formula (a) wherein R.sup.3 and R.sup.5 are each hydro and R.sup.4 is
formyl; or
(g) reacting a compound of Formula 9 with a hydrazide of the formula
H.sub.2 NHNC(O)R.sup.34 (in which R.sup.34 is hydro, aminomethyl,
(C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl) or a
protected derivative thereof, then treating with base and when necessary
deprotecting to give a compound of Formula I in which R.sup.2 is a group
of Formula (b) wherein R.sup.6 is hydro and R.sup.7 is hydro, aminomethyl,
(C.sub.1-4)alkylaminomethyl, di(C.sub.1-4)alkylaminomethyl,
pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholin -4-ylmethyl,
piperazin-1-ylmethyl or 4-(C.sub.1-4)alkylpiperazin-1-ylmethyl; or
(h) reacting a compound of Formula 11:
##STR35##
in which each n, t, R.sup.1, R.sup.4 and R.sup.5 are as defined above
with respect to Formula I with a strong base and then sulfurizing to give
a compound of Formula I in which R.sup.3 is hydro; or
(i) reacting a compound of Formula 11 in which each n, t, R.sup.1, R.sup.4
and R.sup.5 are as defined above with respect to Formula I with a compound
of the formula L--(CH.sub.2).sub.q R.sup.9 in which L is a leaving group
and each q and R.sup.9 are as defined above with respect to Formula I and
then sulfurizing to give a compound of Formula I in which R.sup.2 is a
group of Formula (a) wherein R.sup.3 is --(CH.sub.2).sub.q R.sup.9 ; or
(j) reacting a compound of Formula 11 in which R.sup.4 and R.sup.5 are each
hydro and each n, t, and R.sup.1 are as defined above with respect to
Formula I, with an amino aryl- or alkylsulfonate to give a compound of
Formula I in which R.sup.2 is a group of Formula (a) wherein R.sup.3 is
amino; or
(k) alkylating a compound of Formula 11 in which R.sup.4 and R.sup.5 are
each hydro and each n, t, and R.sup.1 are as defined above with respect to
Formula I, with an appropriately N,N-disubstituted methyleneammonium salt
and then sulfurizing to give a compound of Formula I in which R.sup.2 is a
group of Formula (a) wherein R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl; or
(l) reacting a compound of Formula 16:
##STR36##
in which R.sup.32 is cyano or (C.sub.1-4)alkyloxycarbonyl and each n, t
and R.sup.1 are as defined above with respect to Formula I with a compound
of the formula R.sup.33 C(O)L and then treating with thiocyanic acid to
give a compound of Formula I in which R.sup.2 is a group of Formula (a)
wherein R.sup.3 is hydro, R.sup.5 is cyano or (C.sub.1-4)alkyloxycarbonyl
and R.sup.4 is hydro, (C.sub.1-4)alkyloxycarbonyl or (C.sub.1-4)alkyl; or
(m) reacting a compound of Formula 24:
##STR37##
in which n, t and R.sup.1 are as defined above with respect to Formula I
with isothiocyanate and then treating with base to give a compound of
Formula I in which R.sup.2 is a group of Formula (c) wherein R.sup.8 is
hydro; and
(n) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with a hydrazoic acid derivative to give the compound of Formula I
in which R.sup.5 is 1H-tetrazol-5-yl;
(o) optionally further reducing a compound of Formula I in which R.sup.5 is
cyano to give a compound of Formula I in which R.sup.5 is aminoethyl;
(p) optionally further hydrolyzing a compound of Formula I in which R.sup.5
is cyano to give the compound of Formula I in which R.sup.5 is carbamoyl;
(q) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with ethylenediamine to give the compound of Formula I in which
R.sup.5 is 4,5-dihydroimidazol-2-yl;
(r) optionally further reacting a compound of Formula I in which R.sup.5 is
cyano with a compound of the formula (CH.sub.3).sub.2 AlNR.sup.15 R.sup.16
to give the compound of Formula I in which R.sup.5 is --C(NH)NR.sup.15
R.sup.16, wherein R.sup.15 and R.sup.16 are as defined above with respect
to Formula I;
(s) optionally further reducing a compound of Formula I in which R.sup.5 or
both R.sup.4 and R.sup.5 are ethoxycarbonyl to give a compound of Formula
I in which R.sup.5 or both R.sup.4 and R.sup.5 are hydroxymethyl;
(t) optionally further converting a compound of Formula I in which R.sup.5
is hydroxymethyl to a compound of Formula 28:
##STR38##
in which L is a leaving group and n, t and R.sup.1 are as defined in the
Summary of the Invention with respect to Formula I and reacting the
compound of Formula 28 with an amine of the formula HNR.sup.36 R.sup.37 in
which R.sup.36 and R.sup.37 are independently (C.sub.1-4)alkyl or together
are --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --(CH.sub.2).sub.2
O(CH.sub.2).sub.2 -- or --(C.sub.2).sub.2 NR.sup.38 (CH.sub.2).sub.2 --,
wherein R.sup.38 is hydro or (C.sub.1-4)alkyl, to give a compound of
Formula I in which R.sup.5 is aminomethyl, (C.sub.1-4)alkylaminomethyl,
di(C.sub.1-4)alkylaminomethyl, pyrrolidin-1-ylmethyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, piperazin-1-ylmethyl or
4-(C.sub.1-4)alkylpiperazin-1-ylmethyl;
(u) optionally further reacting a compound of Formula I in which R.sup.4 is
formyl with hydroxylamine hydrochloride and then reducing to give a
compound of Formula I in which R.sup.4 is aminemethyl;
(v) optionally further reacting a compound of Formula I in which R.sup.4 is
formyl with an amine of the formula NH.sub.2 R.sup.10 in the presence of a
chemical reducing agent or catalytic hydrogenation to give a compound of
Formula I in which R.sup.4 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
as defined above with respect to Formula I;
(w) optionally further alkylating a compound of Formula I in which R.sup.4
is formyl to give a compound of Formula I in which R.sup.4 is
1-hydroxy(C.sub.1-4)alkyl;
(x) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.5 or R.sup.6 is amino or R.sup.4, R.sup.5 or R.sup.8 is aminomethyl
with an appropriately substituted amidine to give a corresponding compound
of Formula I in which R.sup.3, R.sup.5 or R.sup.6 is
--NHC(NR.sup.11)NHR.sup.12 or R.sup.4, R.sup.5 or R.sup.8 is --CH.sub.2
NHC(NR.sup.11)NHR.sup.12 wherein R.sup.11 is hydro, acetyl or
tert-butoxycarbonyl and R.sup.12 is acetyl or tert-butoxycarbonyl;
(y) optionally further treating a compound of Formula I in which R.sup.3,
R.sup.5 or R.sup.6 is --NHC(NR.sup.11)NHR.sup.12 or R.sup.4, R.sup.5 or
R.sup.8 is --CH.sub.2 NHC(NR.sup.11)NHR.sup.12, wherein R.sup.11 is hydro,
acetyl or tert-butoxycarbonyl and R.sup.12 is acetyl or
tert-butoxycarbonyl, with acid to give a compound of Formula I in which
R.sup.3, R.sup.5 or R.sup.6 is --NHC(NH)NH.sub.2 or R.sup.4, R.sup.5 or
R.sup.8 is --CH.sub.2 NHC(NH)NH.sub.2 ;
(z) optionally further acylating a compound of Formula I in which R.sup.3,
R.sup.5 or R.sup.6 is amino or R.sup.4, R.sup.5 or R.sup.8 is aminomethyl
with an appropriate acylating agent, or a protected derivative thereof,
and then deprotecting when necessary to give a corresponding compound of
Formula I in which R.sup.3, R.sup.5 or R.sup.6 is --NHR.sup.10 or R.sup.4,
R.sup.5 or R.sup.8 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is
(C.sub.1-4)alkanoyl, trifluoro(C.sub.1-4)alkanoyl, carbamoyl,
(C.sub.1-4)alkyloxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
di(C.sub.1-4)alkylcarbamoyl, amino(C.sub.1-4)alkanoyl,
(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl,
di(C.sub.1-4)alkylamino(C.sub.1-4)alkanoyl or a group selected from aroyl
and heteroaroyl, (which aroyl and heteroaroyl are optionally further
substituted with one to two substituents independently selected from
(C.sub.1-4)alkyloxy, cyano, carboxy and (C.sub.1-4)alkyloxycarbonyl);
(aa) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.5 or R.sup.6 is amino or R.sup.4, R.sup.5 or R.sup.8 is aminomethyl
with (C.sub.1-4)alkyl isocyanate to give a compound of Formula I in which
R.sup.3, R.sup.5 or R.sup.6 is --NHR.sup.10 or R.sup.4, R.sup.5 or R.sup.8
is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is (C.sub.1-4)alkylcarbamoyl;
(bb) optionally further alkylating a compound of Formula I in which
R.sup.3, R.sup.4 and R.sup.5 are each hydro with an appropriately
N,N-disubstituted methyleneammonium salt to give a compound of Formula I
in which R.sup.3 and R.sup.5 are each hydro and R.sup.4 is
di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl;
(cc) optionally further alkylating a compound of Formula I in which R.sup.4
is hydro and R.sup.3 is other than hydro with an appropriately
N,N-disubstituted methyleneammonium salt to give a corresponding compound
of Formula I in which R.sup.5 is di(C.sub.1-4)alkylaminomethyl,
piperidin-1-ylmethyl or morpholin-4-ylmethyl;
(dd) optionally protecting a compound of Formula I in which R.sup.3 is
hydro with a thiol protective group, alkylating with an appropriately
N,N-disubstituted methyleneammonium salt and then deprotecting to give a
compound of Formula I in which R.sup.3 and R.sup.4 are each hydro and
R.sup.5 is di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl or in which R.sup.3 is hydro and both R.sup.4 and
R.sup.5 are di(C.sub.1-4)alkylaminomethyl, piperidin-1-ylmethyl or
morpholin-4-ylmethyl;
(ee) optionally further reacting a compound of Formula I in which R.sup.5
or both R.sup.4 and R.sup.5 are carboxy, or an acid derivative thereof,
with an appropriate amine or thiol to give a compound of Formula I in
which R.sup.5 or both R.sup.4 and R.sup.5 are 1H-tetrazol-5-ylcarbamoyl,
2-(dimethylamino)ethylcarbamoyl, 4-methylpiperazin-1-ylcarbonyl or
2-(dimethylamino)ethylmercapto;
(ff) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.6 or R.sup.8 is hydro with (C.sub.1-4)alkyl acrylate to give a
compound of Formula I in which R.sup.3, R.sup.6 or R.sup.8 is
2-(C.sub.1-4)alkyloxycarbonylethyl;
(gg) optionally further hydrolyzing a compound of Formula I in which
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is
(C.sub.1-4)alkyloxycarbonyl or a group which is further substituted by a
(C.sub.1-4)alkyloxycarbonyl substituent to give a compound of Formula I in
which R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is carboxy or
group which is further substituted by a carboxy substituent;
(hh) optionally further aminating a compound of Formula I in which R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is carboxy or a group which
is further substituted by a carboxy substituent to give a compound of
Formula I in which R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8
is carbamoyl or a group which is further substituted by a carbamoyl
substituent;
(ii) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is carboxy or a group which
is further substituted by a carboxy group with a (C.sub.1-4)alcohol to
give a compound of Formula I in which R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 is (C.sub.1-4)alkyloxycarbonyl or a group that is
further substituted by a (C.sub.1-4)alkyloxycarbonyl group;
(jj) optionally further de-methylating a compound of Formula I in which
R.sup.1 is methoxy and/or in which R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7 or R.sup.8 is a group selected from aroyl, heteraroyl,
aryl(C.sub.1-4)alkyl and heteroaryl(C.sub.1-4)alkyl (which aroyl,
heteroaroyl, aryl and heteroaryl are further substituted with one to two
methoxy substituents) to give a compound of Formula I in which R.sup.1 is
hydroxy and/or R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is a
group selected from aroyl, heteraroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with one to two hydroxy substituents);
(kk) optionally further reacting a compound of Formula I in which R.sup.3,
R.sup.5, R.sup.6 or R.sup.8 is --NHR.sup.10 or in which R.sup.4, R.sup.5
or R.sup.7 is --CH.sub.2 NHR.sup.10, wherein R.sup.10 is a group selected
from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a cyano substituent) with a hydrazoic acid
derivative to give a compound of Formula I in which R.sup.10 is a group
selected from aroyl, heteroaroyl, aryl(C.sub.1-4)alkyl and
heteroaryl(C.sub.1-4)alkyl (which aroyl, heteroaroyl, aryl and heteroaryl
are further substituted with a 1H-tetrazol-5-yl substituent;
(ll) optionally further reacting the corresponding non-salt form of a
compound of Formula I with a pharmaceutically acceptable inorganic or
organic acid or base to give a pharmaceutically acceptable salt;
(mm) optionally further reacting the corresponding acid addition salt or
base addition salt form of a compound of Formula I with a suitable base or
acid, respectively, to give the free acid or free base; and
(nn) optionally further separating a mixture of stereoisomers of a compound
of Formula I to give a single stereoisomer.
Compounds of Formula 3:
A preferred method for making a compound of Formula 3 in which n is 1 and
the amine is attached at the .beta.-position as the individual
(S)-enantiomer is depicted by the following Reaction Scheme X:
##STR39##
in which each t and R.sup.1 are as defined in the Summary of the Invention
with respect to Formula I.
Compounds of Formula 3 in which n is 1 and the amine is attached at the
.beta.-position can be prepared as the individual (S)-enantiomer (Formula
3(a)) by hydrolyzing a compound of Formula 29. The hydrolysis can be
carried out with an aqueous base (e.g., lithium hydroxide monohydrate,
sodium hydroxide, potassium hydroxide, potassium carbonate, etc.,
preferably lithium hydroxide monohydrate) in a suitable solvent, typically
an alcohol (e.g., methanol, ethanol, isopropanol) and preferably methanol,
at 25.degree. to 100.degree. C., preferably reflux, and requires 0.5 to 5
hours.
Compounds of Formula 29 are prepared by hydrogenolysis of a compound of
Formula 30. The hydrogenolysis can be accomplished by a two step process
comprising (i) hydrogenating a compound of Formula 30 until conversion to
the corresponding 1-naphthol is complete and (ii) adding sulfuric acid and
continuing hydrogenation to give the compound of Formula 29. Hydrogenation
of the compound of Formula 30 to the 1-naphthol is carried out in the
presence of an appropriate catalyst (e.g., Pearlman's catalyst, palladium
on carbon, etc., preferably Pearlman's catalyst) in acetic acid or
trifluoroacetic acid (TFA), preferably acetic acid, at 1 to 130 psig and
10.degree. to 30.degree. C. and requires 0.5 to 4 hours. Hydrogenation of
the 1-naphthol is carried out by adding 1 to 10 equivalents, preferably 4
to 6 equivalents, of sulfuric acid or perchloric acid and continuing the
hydrogenation under the same conditions for 3 to 120 hours. Alternatively,
the hydrogenolysis is effected by a single step process comprising
hydrogenating the compound 30 in the presence of an appropriate catalyst
and either sulfuric acid or perchloric acid in acetic acid. The single
step hydrogenolysis is carried out at 1 to 130 psig and 10.degree. to
30.degree. C. and requires 3 to 120 hours.
Compounds of Formula 30 are prepared from compounds of Formula 31 by an
intramolecular Friedel-Crafts reaction. The reaction is effected by
converting a compound of Formula 31 to the corresponding acid chloride and
then treating the acid chloride with an appropriate Lewis acid (e.g.
aluminum chloride, hydrogen fluoride, etc., preferably aluminum chloride)
to give the compound of Formula 30. Conversion to the acid chloride can be
carried out with an appropriate chlorinating agent (e.g., phosphorus
pentachloride, thionyl chloride, oxalyl chloride, etc., preferably
phosphorus pentachloride) in methylene chloride at 0.degree. to 10.degree.
C., preferably at 5.degree. to 10.degree. C., and requires 0.5 to 2 hours.
The treatment with Lewis acid and the resultant ring closure is carried
out at 0.degree. to 10.degree. C., preferably at 5.degree. to 10.degree.
C., and requires 1 to 3 hours. Preferably, the crude product is isolated
by crystallization from a methanol/water or isopropanol/water mixture; and
then, if necessary, recrystallization from a toluene/heptane mixture.
Compounds of Formula 31 are prepared by hydrogenolysis of a compound of
Formula 32. The hydrogenolysis is carried out by hydrogenating in the
presence of an appropriate catalyst (e.g., 20% palladium hydroxide on
carbon (Pearlman's catalyst), palladium on carbon, etc., preferably
Pearlman's catalyst) and 1 to 5 equivalents, preferably 1.5 to 2
equivalents, of sulfuric acid, in a glacial acetic acid at 1 to 60 psig
and 5.degree. to 30.degree. C. and requires 2 to 48 hours. Compounds of
Formula 32 are prepared via a Friedel-Crafts alkylation of optionally
substituted benzene with N-(trifluoroacetyl)-L-aspartic anhydride. The
alkylation is carried out in the presence of a Lewis acid (e.g., aluminum
chloride, tin chloride, hydrogen fluoride, etc., preferably aluminum
chloride) and in a suitable solvent (e.g., methylene chloride, etc.,
preferably methylene chloride) at 25.degree. to 40.degree. C., preferably
at reflux, and requires 2 to 5 hours.
N-(Trifluoroacetyl)-L-aspartic anhydride is prepared by reacting L-aspartic
acid with trifluoroacetic anhydride (TFAA). The reaction is highly
exothermic and when more than 100 g amounts of reactants are employed, it
must be conducted under conditions such that the liberation of heat is
controlled. For example, a convenient method for carrying out the reaction
is by heating 2 to 4 equivalents, preferably 2.3 to 2.5 equivalents, of
TFAA to between 30.degree. and 40.degree. C., preferably to reflux, and
then adding 1 equivalent of L-aspartic acid at a rate such that the
reaction readily proceeds but the heat generated by the reaction can be
dissipated by reflux. Preferably the L-aspartic acid is added to the TFAA
as a solution in TFA over 30 to 60 minutes.
Proceeding as described in Reaction Scheme XIII but substituting D-aspartic
acid for L-aspartic acid, the (R)-enantiomer of the compound of Formula
3(a) can be prepared. Further details of the reaction steps set forth
above for Reaction Scheme XII are provided in Example 6.
Compounds of Formula 6:
Compounds of Formula 6 can be prepared by reducing a corresponding compound
of Formula 7. The reduction is carried out with a chemical reducing agent
such as sodium borohydride in a suitable solvent, typically an alcohol
(e.g., ethanol, methanol, isopropanol, any appropriate mixture of suitable
alcohols, etc.) or lithium aluminum hydride (LAH) in a suitable solvent
(e.g., diethyl ether, THF, 1,2-dimethoxyethane, any appropriate mixture of
suitable solvents, etc.) at 0.degree. to 80.degree. C. and requires 1 to 2
hours (for further details see Example 1, infra.).
An alternative method for making compounds of Formula 6 in which n is 0 or
1 and the hydroxy is attached at the .beta.-position is depicted by the
following Reaction Scheme XI:
##STR40##
in which each n is 0 or 1 and t and R.sup.1 is as defined in the Summary
of the Invention with respect to Formula I.
Compounds of Formula 6 in which n is 0 or 1 and the hydroxy is attached at
the .beta.-position (Formula 6(b)) can be prepared by reacting a compound
of Formula 34 with 3-chloroperoxybenzoic acid (m-CPBA) to give an epoxide
of Formula 33 and then reducing the epoxide to give the corresponding
.beta.-alcohol. The reaction with m-CPBA is carried out in a suitable
solvent (e.g., benzene, methylene chloride, chloroform, any appropriate
mixture of suitable solvents, etc.) at 0.degree. to 20.degree. C.,
preferably approximately 0.degree. C., and requires 0.5 to 5 hours.
Reduction of the epoxide can be effected by catalycic hydrogenation (e.g.,
H.sub.2, 10% palladium on carbon; etc.) in a suitable solvent (e.g., ethyl
acetate, ethanol, isopropanol, any appropriate mixture of suitable
solvents, etc.).
Compounds of Formula 34 can be prepared by reacting an .alpha.-alcohol of
Formula 6(a) with p-toluenesulfonic acid in a suitable solvent (e.g.,
benzene, toluene, dichloroethane, methylene chloride, etc.) at 20.degree.
to 110.degree. C., typically at 60.degree. to 100.degree. C. and
preferably at approximately 80.degree. C., for 1 to 5 hours. Further
details of the reaction steps set forth in this and the preceding
paragraph are provided in Example 2.
Compounds of Formula I can be prepared as their individual stereoisomers
from the individual stereoisomers of starting material. The starting
material can be prepared as individual stereoisomers by any of the
resolution techniques described above or by any method known to one of
ordinary skill in the art. For example, compounds of Formula 6 can be
prepared as their individual stereoisomers by kinetic enzymatic resolution
with a suitable enzyme (e.g., porcine pancreatic lipase, candida
cylindracea, pancreatin, etc.).
Alternatively, certain starting materials in the process for preparing
compounds of Formula I can be prepared as their individual stereoisomers
by chiral synthesis. For example, compounds of Formula 6 can be prepared
as their individual stereoisomers by chiral reduction of the corresponding
compound of Formula 7. Compounds of Formula 6, wherein the hydroxy is
attached at the .alpha.-position, can be prepared as the (R)-enantiomer by
reducing the corresponding compound of Formula 7 with borohydride in the
presence of (S)-1-aza-2-boro-3-oxa-4,4-diphenyl›3.3.0!bicyclooctane in
THF. Similarly, the (S)-enantiomer can be prepared by reducing the
compound of Formula 7 in the presence of
(R)-1-aza-2-boro-3-oxa-4,4-diphenyl›3.3.0!bicyclooctane.
Compounds of Formula 6, wherein the hydroxy is attached at the
.beta.-position, can be prepared as the (R)-enantiomer by reducing the
corresponding compound of Formula 7 with lithium aluminum hydride in the
presence of (1R,2S)-N-methylephedrine and 2-ethylaminopyridine. The
reaction is carried out in diethyl ether at -78.degree. to -65.degree. C.,
preferably approximately -78.degree. C., and requires 2 to 3 hours (for
further details see Example 3, infra.). Similarly, the (S)-enantiomer can
be prepared by reducing the compound of Formula 7 in the presence of
(1S,2R)-N-methylephedrine and 2-ethylaminopyridine. Compounds of Formula
7:
Compounds of Formula 7 are available commercially or can be readily made by
those of ordinary skill in the art. For example, suitable compounds of
Formula 7 can be obtained can be prepared by oxidizing an available
compound of Formula 6. The oxidation of the compound of Formula 6 can be
effected with an appropriate oxidizing agent (e.g., Dess-Martin reagent)
in a suitable solvent (e.g., THF, methylene chloride, etc.) at 20.degree.
to 50.degree. C.
Compounds of Formula 7 in which n is 0 or 1 and the oxo is attached at the
.alpha.-position is depicted by the following Reaction Scheme XII:
##STR41##
in which n is 0 or 1 and t and R.sup.1 are as defined in the Summary of
the Invention with respect to Formula I.
Compounds of Formula 7 in which n is 0 or 1 and the oxo is attached at the
.alpha.-position (Formula 7(a)) can be prepared by reacting a compound of
Formula 35 with a Lewis acid (e.g., aluminum chloride, aluminum bromide,
boron trifluoride, hydrogen fluoride, etc.) in a suitable solvent (e.g.,
methylene chloride, carbon disulfide, nitrobenzene, any appropriate
mixture of suitable solvents, etc.). The reaction is carried out in the
presence of carbon disulfide at 20.degree. to 45.degree. C., typically at
30.degree. to 45.degree. C. and preferably at approximately 45.degree. C.,
and requires 1 to 8 hours.
Compounds of Formula 35 can be prepared by reacting a compound of Formula
36 with a chlorinating agent (e.g., oxalyl chloride, thionylchloride,
phosphorus pentachloride, etc., preferably oxalyl chloride) in a suitable
solvent (e.g., methylene chloride, dichloroethane, any appropriate mixture
of suitable solvents, etc.) at 20.degree. to 40.degree. C., typically at
10.degree. to 30.degree. C. and preferably at approximately 20.degree. C.,
for 2 to 18 hours. Further details of the reaction steps set forth in this
and the preceding paragraph are provided in Example 1.
Compounds of Formula 36 in which n is 0 can be prepared by reacting
optionally substituted bromo- or iodobenzene with ethyl acrylate in a
suitable solvent (e.g., DMF, dimethylacetamide, DMPU, any appropriate
mixture of suitable solvents, etc.), reducing and then hydrolyzing. The
reaction with the ethyl acrylate is carried out in the presence of a
suitable palladium catalyst (e.g., bis(triphenylphosphine palladium(II)
chloride) at 70.degree. to 110.degree. C., typically at 80.degree. to
100.degree. C. and preferably at approximately 90.degree. C., and requires
4 to 72 hours. The reduction can be effected by catalytic hydrogenation
under standard conditions. The hydrolysis can be effected with aqueous
base or acid in a suitable solvent (e.g., aqueous sodium hydroxide in
ethanol, aqueous sulfuric acid in dioxane, etc.).
Similarly, compounds of Formula 36 in which n is 1 can be prepared by
reacting optionally substituted bromo- or iodobenzene with 3-butyl-1-ol in
a suitable solvent (e.g., DMF and triethylamine, etc.), reducing and
oxidizing. The reaction with the 3-butyn-1-ol is carried out in the
presence of a suitable palladium catalyst (e.g., bis(triphenylphosphine
palladium(II) chloride) at 80.degree. to 90.degree. C., preferably at
approximately 85.degree. C., and requires 4 to 24 hours. The subsequent
reduction can be effected by catalytic hydrogenation. The oxidation can be
effected with a suitable oxidizing agent (e.g., potassium dichromate(VI),
potassium permanganate, etc.).
A method for making compounds of Formula 7 in which n is 1 and the oxo is
attached at the .beta.-position is depicted by the following Reaction
Scheme XIII:
##STR42##
in which each t and R.sup.1 is as defined in the Summary of the Invention
with respect to Formula I.
Compounds of Formula 7 in which n is 1 and the oxo is attached at the
.beta.-position (Formula 7(b)) can be prepared by converting a compound of
Formula 38 to the corresponding acid chloride (Formula 37) and then
reacting the acid chloride with ethylene in the presence of a Lewis acid
(e.g., aluminum chloride, boron trifluoride, aluminum bromide, etc.). The
conversion to the acid chloride is carried out with an appropriate
chlorinating agent (e.g., thionyl chloride, oxalyl chloride, phosphorus
pentachloride, etc.) and in a suitable solvent (e.g., methylene chloride,
dichloroethane, any appropriate mixture of suitable solvents, etc.) at
20.degree. to 40.degree. C., typically at 20.degree. to 30.degree. C. and
preferably at approximately 20.degree. C., and requires 2 to 18 hours. The
reaction with ethylene is carried out in a suitable solvent (e.g.,
methylene chloride, carbon disulfide, any appropriate mixture of suitable
solvents, etc.) and by adding the acid chloride to the Lewis acid at a
rate such that the reaction mixture remains below -40.degree. C.,
preferably below -60.degree. C., and then bubbling the mixture with
ethylene gas for 0.1 to 0.5 hours at -78.degree. to -40.degree. C.,
typically at -60.degree. to -78.degree. C. and preferably at approximately
-78.degree. C. Further details of the reaction steps set forth in this
paragraph are provided in Example 3.
A method for making compounds of Formula 7 in which n is 2 and the oxo is
attached at the .beta.-position is depicted by the following Reaction
Scheme XIV:
##STR43##
in which each t and R.sup.1 is as defined in the Summary of the Invention
with respect to Formula I.
Compounds of Formula 7 in which n is 2 and the oxo is attached at the
.beta.-position (Formula 7(d)) can be prepared by reacting a compound of
Formula 39 with sodium nitrite in a suitable solvent (e.g., acetic
acid-water, trifluoroacetic acid-water, acetic acid-ethanol, etc.). The
reaction is carried out at -15.degree. to 20.degree. C., typically at
-10.degree. to 0.degree. C. and preferably at approximately -0.degree. C.,
and requires 1 to 18 hours. Compounds of Formula 39 are prepared by
reacting a compound of Formula 7(c) with trimethylsilyl cyanide (TMSCN)
and zinc chloride neat or in a suitable solvent (e.g., methylene chloride,
any appropriate mixture of suitable solvents, etc.) to give a compound of
Formula 40 and then reducing. The reaction with TMSCN is carried out at
0.degree. to 20.degree. C., typically at 10.degree. to 20.degree. C. and
preferably at approximately 20.degree. C., and requires 1 to 18 hours. The
reduction can be effected with a chemical reducing agent in a suitable
solvent. Further details of the reaction steps set forth in this and the
preceding paragraph is provided in Example 4.
A method for making compounds of Formula 7 in which n is 2 and the oxo
attached at the .gamma.-position is described by the following Reaction
Scheme XV:
##STR44##
in which each t and R.sup.1 is as defined in the Summary of the Invention
with respect to Formula I.
Compounds of Formula 7 in which n is 2 and the oxo is attached at the
.gamma.-position (Formula 7(e)) can be prepared by treating a compound of
Formula 42 with sodium ethoxide to effect ring closure and give a compound
of Formula 41, hydrolyzing the compound of Formula 41 to give the
corresponding acid and then decarboxylating the acid. The reaction with
sodium ethoxide and the resultant ring closure is carried in a suitable
solvent (e.g., toluene, ethanol, any appropriate mixture of suitable
solvents, etc.) at 80.degree. to 110.degree. C., typically at 90.degree.
to 110.degree. C. and preferably at approximately 100.degree. C., and
requires 3 to 18 hours. The hydrolysis can be effected by heating in an
aqueous base or acid. The decarboxylation can be effected by heating to
80.degree. to 125.degree. C., typically at 90.degree. to 110.degree. C.
and preferably at approximately 100.degree. C., and requires 4 to 8 hours.
Compounds of Formula 42 can be prepared by reducing a compound of Formula
43. The reduction can be effected by catalytic hydrogenation (e.g.,
H.sub.2, 10% palladium on carbon, etc.).
Compounds of Formula 43 can be prepared by reacting optionally substituted
dibromo or diiodo benzene with ethyl acrylate. The reaction with the ethyl
acrylate is carried out in the presence of a suitable palladium catalyst
(e.g., bis(trlphenylphosphine palladium(II) chloride, etc.) and in a
suitable solvent (e.g., DMF, any appropriate mixture of suitable solvents,
etc.) at 5.degree. to 130.degree. C., typically at 85.degree. to
105.degree. C. and preferably at approximately 95.degree. C., and requires
72 to 168 hours. Further details of the reaction steps set forth in this
and the preceding paragraph are provide in Example 5.
Preparation of Compounds of Formula II:
A method for making compounds of Formula II in which R.sup.18 is a group of
Formula (d) wherein R.sup.21 is --CH.sub.2 NR.sup.25 R.sup.26 is depicted
by the following Reaction Scheme XVI:
##STR45##
in which each n, t, R.sup.1, R.sup.25 and R.sup.26 are as defined in the
Summary of the Invention with respect to Formula II.
Compounds of Formula II in which R.sup.18 is a group of Formula (d) wherein
R.sup.21 is --CH.sub.2 NR.sup.25 R.sup.26 (Formula 44) can be prepared by
reacting a compound of Formula I(a) in which R.sup.5 is --CH.sub.2
NHR.sup.25 (Formula 45) with a protected derivative of an L-amino acid in
a suitable solvent (e.g., DMF, methylene chloride, THF, any appropriate
mixture of suitable solvents, etc.) and then removing all protective
groups present. The reaction with the L-amino acid is carried out in the
presence of a non-nucleophilic base (e.g., DIEA,
N,N-dicyclohexylmethylamine, etc.) and a peptide coupling agent (e.g.,
PyBOP, benzotriazol-1-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate, N,N-dicyclohexylcarbodimide,
bromotris(pyrrolidin-1-yl)phosphonium hexafluorophosphate, etc.) at
20.degree. to 80.degree. C., preferably approximately 20.degree. C., and
requires 8 to 24 hours (for further details see Example 51, infra.).
Protected L-amino acids are prepared by reacting an appropriate L-amino
acid with a suitable protecting agent (e.g., di-tert-butyldicarbonate,
9-fluorenylmethylsuscinimidylcarbonate, etc.). For example, the protected
derivative of L-lysine is prepared by reacting L-lysine with
di-tert-butyldicarbonate in a suitable solvent (e.g., THF, DMF, any
appropriate mixture of suitable solvents, etc.). The reaction is carried
out at 0.degree. to 20.degree. C., preferably at approximately 20.degree.
C., and requires 8 to 48 hours. Removal of the protective groups can be
effected by acid hydrolysis (e.g., 15% hydrogen chloride) in a suitable
solvent (e.g., ethyl acetate, 1,2-dimethoxyethane, any appropriate mixture
of suitable solvents, etc.). 9-Fluorenylmethoxycarbonyl protective groups
can be removed with piperidine in DMF. Carbobenzyloxy protective groups
can be removed by hydrogenating with palladium on carbon.
Proceeding similarly, compounds of Formula II in which R.sup.18 is a group
of Formula (d) wherein R.sup.20 is --CH.sub.2 NR.sup.25 R.sup.26 are
prepared from compounds of Formula I(a) in which R.sup.4 is --CH.sub.2
NHR.sup.25. Compounds of Formula II in which R.sup.18 is a group of
Formula (d) wherein R.sup.21 is --NR.sup.25 R.sup.26 are prepared from
compounds of Formula I(a) in which R.sup.5 is --NHR.sup.25. Compounds of
Formula II in which R.sup.18 is a group of Formula (e) wherein R.sup.23 is
--CH.sub.2 NR.sup.25 R.sup.26 are prepared from compounds of Formula I(b)
in which R.sup.7 is --CH.sub.2 NHR.sup.25. Compounds of Formula II in
which R.sup.18 is a group of Formula (d) wherein R.sup.19 is --NR.sup.25
R.sup.26 can be prepared from a compound of Formula I(a), wherein R.sup.3
is --NHR.sup.25. Compounds of Formula II in which R.sup.18 is a group of
Formula (f) wherein R.sup.15 is --NR.sup.25 R.sup.26 can be prepared from
a compound of Formula I(c), wherein R.sup.8 is --NHR.sup.25.
Preparation of Compounds of Formula III:
A method for making compounds of Formula III in which R.sup.27 is a group
of Formula (g) is depicted by the following Reaction Scheme XVII:
##STR46##
in which each n, t, R.sup.1 and R.sup.28 are as defined in the Summary of
the Invention with respect to Formula III.
Compounds of Formula III in which R.sup.27 is a group of Formula (g)
(Formula 46) can be prepared by reacting a compound of Formula I(a)
wherein R.sup.3 is hydro (Formula 48) with a compound of Formula 47, or a
protected derivative thereof, in a suitable solvent (e.g., ethyl acetate,
ethylenedichloride, THF, any appropriate mixture of suitable solvents,
etc.) and then removing all protective groups present. The reaction with
the compound of Formula 47 is carried out at 20.degree. to 110.degree. C.,
preferably approximately 80.degree. C., for 1 to 4 hours.
Compounds of Formula 47 can be prepared by reacting a compound of the
formula X--SR.sup.28, in which X is halo, or the protected derivatives
thereof, with potassium phthalimide in a suitable solvent (e.g.,
ethylenedichloride, carbon tetrachloride, 1,1,1,2-tetrachloroethane,
etc.). The reaction is carried out at -30.degree. to 20.degree. C.,
preferably approximately -20.degree. C., and requires 1 to 3 hours.
Compounds of the formula X--SR.sup.28 can be readily prepared by those of
skill in the art. For example, a compound of the formula X--SR.sup.28 in
which X is bromo and R.sup.28 is
2-tert-butoxycarbonyl-2-(tert-butyloxycarbonylamino)ethyl can be prepared
by reacting N-(tert-butoxycarbonyl)cystine with bromine in a suitable
solvent (e.g., dichloroethane, etc.). The reaction is carried out at
-40.degree. to 20.degree. C., preferably at approximately -23.degree. C.,
and requires 1 to 3 hours. Further details of the reaction steps set forth
by Reaction Scheme XVII is provided in Example 52, infra.
Proceeding similarly, compounds of Formula III in which R.sup.27 is a group
of Formula (h) are prepared from compounds of Formula I(b). Compounds of
Formula III in which R.sup.27 is a group of Formula (i) are prepared from
compounds of Formula I(c) in which R.sup.8 is hydro.
EXAMPLE 1
5,6-Difluoro-1-hydroxyindane
The following is the preparation of a compound of Formula 6 in which n is
0, t is 2 and R.sup.1 is fluoro and at the 5- and 6-position.
3-(3,4-Difluorophenyl)propionic acid (80.0 g, 0.43 mol) was dissolved in 3
drops of DMF and 350 mL of methylene chloride. Oxalyl chloride (75 mL,
0.860 mol) was added and the mixture was stirred under nitrogen at room
temperature for approximately 3 hours. Excess oxalyl chloride was removed
by evaporation and the residue was co-evaporated twice with 200 mL of
carbon tetrachloride giving 95.0 g of residue as an oil.
Aluminum chloride (200 g) was suspended in 800 mL of carbon disulfide and
the suspension was cooled to 0.degree. C. A solution of the residue in 300
mL of carbon disulfide was added to the suspension over 20 minutes and the
mixture was stirred at reflux for 4 hours. The mixture was poured onto 2
kg of crushed ice and the aqueous layer was extracted ethyl acetate
(3.times.300 mL). The carbon disulfide layer and ethyl acetate extract
were both dried over magnesium sulfate, filtered and then combined. The
solvents were removed by evaporation and the residue was crystallized from
isopropyl ether giving 54.3 g of 5,6-difluoroindan-1-one as a solid. The
mother liquor was purified by column chromatography on silica gel
(elution: 10% ethyl acetate/hexane) giving an additional 5.2 g of
5,6-difluoroindan-1-one.
5,6-Difluoroindan-1-one (59.3 g, 0.353 mol) was dissolved in 1 L of ethanol
and sodium borohydride (6.68 g, 0.176 mol) was added. The mixture was
stirred for 48 hours and the ethanol was removed by evaporation under
reduced pressure. The residue was partitioned between diethyl ether and
water and the mixture was acidified with 1N hydrochloric acid. The mixture
was dried over magnesium sulfate and filtered. The solvents were
evaporated giving 5,6-difluoro-1-hydroxyindane (59.8 g) as an oil.
Proceeding as in Example 1 but substituting a different starting material
for 3-(3,4-difluorophenyl)propionic acid, the following compounds of
Formula 6 were made:
substituting 3-(3,5-difluorophenyl)propionic acid gave
5,7-difluoro-1-hydroxyindane, m.p. 102.degree.-103.degree. C.;
substituting 4-(2,4-difluorophenyl)butyric acid gave
5,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene as an oil;
substituting 4-(3,4-difluorophenyl)butyric acid gave
6,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene as an oil;
substituting 4-(4-fluorophenyl)butyric acid gave
7-fluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene as an oil;
substituting 4-(3-fluorophenyl)butyric acid gave
6-fluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene as an oil; and
substituting 4-(3,5-difluorophenyl)butyric acid gave
6,8-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene, m.p.
102.degree.-103.degree. C.
EXAMPLE 2
5,6-difluoro-2-hydroxyindane
The following is the preparation of a compound of Formula 6 in which n is
0, t is 2 and R.sup.1 is fluoro at the 5- and 6-position.
5,6-Difluoro-1-hydroxyindane (59.8 g, 356 mmol), prepared as in Example 1,
was dissolved in 600 mL of benzene and p-toluenesulfonic acid monohydrate
(3.36 g, 17.66 mol) was added. The mixture was heated to 120.degree. C.,
distilled for approximately 2 hours and then allowed to cool. Saturated
sodium bicarbonate solution was added and the benzene layer was dried over
magnesium sulfate. The benzene layer was then filtered and the filter
residue was washed with diethyl ether.
The benzene/diethyl ether mixture was cooled to 0.degree. C. and m-CPBA
(75.5 g, 0.35 mol) was added over 15 minutes. The mixture was stirred at
room temperature for 5 hours. The diethyl ether was removed by rotary
evaporation, 400 mL of methylene chloride was added and the mixture was
stirred for 2 hours. Additional m-CPBA (30.0 g, 0.14 mol) was added and
the mixture was stirred for 2 hours. The mixture was cooled to 0.degree.
C. and potassium iodide (45 g) in 150 mL of water was added. The mixture
was stirred for approximately 15 minutes and then sodium thiosulfate (40
g) in 150 mL of water was added. Kugelrohr distillation (bp
60.degree.-90.degree. C. ›0.1 mm!)) gave 30 g of impure
1,2-epoxy-5,6-difluoroindane as an oil.
Impure 1,2-epoxy-5,6-difluoroindane (4.5 g) was dissolved in 100 mL of
ethanol and hydrogenated over 10% palladium on carbon (450 mg) for 15
hours. The mixture was filtered and evaporation gave
5,6-difluoro-2-hydroxyindane (2.72 g, 15.9 mmol), m.p.
57.degree.-58.degree. C.
Proceeding as in Example 2 but substituting a different starting material
for 5,6-difluoro-1-hydroxyindane, the following compounds of Formula 6
were made:
substituting 5,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene gave
5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
93.degree.-94.degree. C.;
substituting 4,6-difluoro-1-hydroxyindane gave
4,6-difluoro-2-hydroxyindane, m.p. 52.degree.-56.degree. C.;
substituting 6,7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene gave
6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene as an oil; and
substituting 6,8-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene gave
6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene.
EXAMPLE 3
(R)-5,7-Difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene
The following is the preparation of a compound of Formula 6 in which t is 2
and R.sup.1 is fluoro at the 5- and 7-position.
A mixture 3,5-difluorophenylacetic acid (100 g, 0.58 mmol) and thionyl
chloride (13.7M, 100 mL, 1.37 mol) was stirred for 15 hours at room
temperature. Evaporation gave 3,5-difluorophenylacetyl chloride as an oily
residue. A stirred suspension of aluminum chloride (154 g, 1.16 mmol) in 1
L of methylene chloride was cooled to -65.degree. C. and the acid chloride
in 200 mL of methylene chloride was added dropwise such that the reaction
temperature did not exceed -60.degree. C. Ethylene gas was bubbled through
the suspension at a rapid rate for 10 minutes at -65.degree. C. The
reaction mixture was allowed to warm to 0.degree. C. over 2 hours, then
cooled to -10.degree. C. and treated with 500 mL of water. The organic
layer was separated, washed with 100 mL of aqueous sodium chloride, and
then dried over magnesium sulfate. The mixture was filtered and the
filtrate was concentrated under reduced pressure. Distillation of the
residue in vacuo (bp 90.degree.-110.degree. C. ›1.0 to 0.7 mm!) gave a
clear distillate. Redistillation (bp 100.degree.-105.degree. C. ›0.3 mm!)
gave 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-one (73.56 g, 0.342 mol)
as a white solid, m.p. 46.degree. C.
A solution of (1R,2S)-N-methylephedrine (81.3 g, 0.454 mol) in 1.2 L of
anhydrous diethyl ether was added to lithium aluminum hydride (1.0M in
diethyl ether, 416 mL, 0.416 mol) over 45 minutes. The mixture was heated
under reflux for 1 hour and then allowed to cool to room temperature. A
solution of 2-ethylaminopyridine (110.7 g, 0.907 mol) in 100 mL of
anhydrous diethyl ether was added over 45 minutes. The mixture was heated
under reflux for 1 hour and then cooled to -65.degree. C. A solution of
5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2-one (23.0 g, 0.107 mol) in
100 mL of diethyl ether was added dropwise such that the reaction
temperature did not exceed -60.degree. C. The mixture was stirred at
-65.degree. C. to -68.degree. C. for 3 hours and then 100 mL of methanol
was added such that the reaction temperature did not exceed -60.degree. C.
The mixture was stirred at -65.degree. C. to -68.degree. C. for 10
minutes, then allowed to warm to -20.degree. C., and 3.0 L of 3N
hydrochloric acid was added such that the reaction temperature did not
exceed 35.degree. C. The diethyl ether layer was separated, washed with
200 mL of saturated sodium chloride, and dried over magnesium sulfate. The
mixture was filtered and the filtrate concentrated under reduced pressure.
Crystallization from 20 mL of diethyl ether and 200 mL of hexane and
drying in vacuo gave
(R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (10.87 g, 0.05
mol), m.p. 85.degree. C. ›.alpha.!.sub.D.sup.25 =+36.03.degree. (c=1.59,
CHCl.sub.3).
Proceeding as in Example 3 but substituting a different starting material
for 3,5-difluorophenylacetic acid, the following compounds of Formula 6
were made:
substituting 3-fluorophenylacetic acid gave
(R)-7-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
59.degree.-61.degree. C., ›.alpha.!.sub.D.sup.25 =+48.8.degree. (c=2.0,
CHCl.sub.3);
substituting 4-fluorophenylacetic acid gave
(R)-6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene,
›.alpha.!.sub.D.sup.25 =+49.2.degree. (c=1.84, CHCl.sub.3);
substituting phenylacetic acid gave
(R)-1,2,3,4-tetrahydro-2-hydroxynaphthalene, as an oil,
›.alpha.!.sub.D.sup.25 =+62.2.degree. (c=1.6, CHCl.sub.3); and
substituting 3,4-difluorophenylacetic acid gave
(R)-6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
88.degree.-92.degree. C., ›.alpha.!.sub.D.sup.25 =+39.0.degree. (c=2.2,
CHCl.sub.3).
Proceeding as in Example 3 but substituting (1S, 2R)-N-methylephedrine for
(1R, 2S) -N-methylephedrine, gave
(S)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
84.degree.-85.degree. C., ›.alpha.!D.sup.25 =-37.4.degree. (c=2.6,
CHCl.sub.3).
Proceeding as in Example 3 but substituting a different starting material
for 3,5-difluorophenylacetic acid and reducing without
(1R,2S)-N-methylephedrine or 2-ethylaminopyridine present, the following
compounds of Formula 6 were made:
substituting 4-bromophenylacetic acid gave
6-bromo-1,2,3,4-tetrahydro-2-hydroxynaphthalene as an oil;
substituting 4-chlorophenylacetic acid gave
6-chloro-1,2,3,4-tetrahydro-2-hydroxy-naphthalene as an oil;
substituting 3-chlorophenylacetic acid gave
7-chloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
79.degree.-81.degree. C.;
substituting 3,5-dichlorophenylacetic acid gave
5,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
84.degree.-86.degree. C.;
substituting 3,5-difluorophenylacetic acid gave
5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene;
substituting 3,4-difluorophenylacetic acid gave
6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene,;
substituting 3,4-dichlorophenylacetic acid gave
6,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, m.p.
103.degree.-105.degree. C.; and
substituting 4-fluorophenylacetic acid gave
6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene.
EXAMPLE 4
1,3-Difluoro-6,7,8,9-tetrahydro-6-hydroxy-5H-banzocycloheptene
The following is the preparation of a compound of Formula 6 in which t is 2
and R.sup.1 is fluoro at the 1- and 3-position.
A mixture of 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-one (4.0 g, 22.0
mmol), zinc iodide (22.0 mg, 68.9 mmol) and trimethylsilyl cyanide (3.23
mL, 24.2 mmol) was stirred under argon at room temperature for 18 hours.
The TMSCN was evaporated under vacuum and the residue (6.13 g) was
dissolved in 45 mL of anhydrous diethyl ether. Lithium aluminum hydride
(1.0M, 24.2 mL, 24.2 mmol) in diethyl ether was added to the solution at
such a rate that gentle reflux was maintained. The mixture was stirred at
room temperature for 1 hour and then 0.84 mL of water, 0.84 mL of 15%
sodium hydroxide and 1.63 mL of additional water were added sequentially.
The aqueous layer was stirred for 10 minutes, filtered and extracted with
diethyl ether. The combined extracts were dried over magnesium sulfate and
concentrated giving 4.21 g of residue. Purification of the residue by
flash chromatography (elution: 10% methanol/methylene chloride) gave
1-aminomethyl-5,7-difluoro-1-hydroxy-1,2,3,4-tetrahydronaphthalene (3.67
g, 17.2 nmol).
A mixture of 1-aminomethyl-5,7-difluoro-1-hydroxy-1,2,3,4-tetrahydro
naphthalene (3.58 g, 16.8 mmol) and sodium nitrite (2.32 g, 33.6 mmol) in
8 mL of acetic acid and 20 mL of water was heated at -5.degree. C. and
then allowed to warm to room temperature and stirred for 18 hours. The
solvents were removed by evaporation and 3.14 g of the residue was
purified by flash chromatography (elution: 50% hexane/methylene chloride)
giving 1.8 g of residue. A mixture of the purified residue and LAH (9.2
mL, 9.2 mmol) in THF was stirred at 0.degree. C. for 18 hours and then
0.64 mL of water, 0.64 mL of 15% sodium hydroxide and 1.3 mL of additional
water were added sequentially. The THF layer was dried over magnesium
sulfate and concentrated to 1.8 g of residue. Purification by flash
chromatography (elution: methylene chloride) gave
1,3-difluoro-6,7,8,9-tetrahydro-6-hydroxy-5H-benzocycloheptene (1.4 g,
7.06 mmol).
EXAMPLE 5
1,3-Difluoro-6,7,8,9-tetrahydro-7-hydroxy-5H-benzocycloheptene
The following is the preparation of a compound of Formula 6 in which t is 2
and R.sup.1 is fluoro and the 1- and 3-position.
A mixture of 1,2-dibromo-3,5-difluorobenzene (24.7 g, 91.6 mmol),
bis(triphenylphosphine)palladium(II) chloride (2.57 g, 3.66 mmol) and
triethylamine (51.0 mL, 366 mmol) in 300 mL of DMF was stirred under argon
at approximately 85.degree. C. for 15 minutes. Hydrazine hydrate (366
.mu.L, 7.54 mmol) was added and the mixture was stirred for an additional
10 minutes. Ethyl acrylate (39.7 mL, 366 mmol) was added and the mixture
was stirred under argon at approximately 85.degree. C. for approximately
144 hours. The solvents were removed by evaporation under reduced pressure
and the residue was dissolved in 1.0 L of ethyl acetate. The ethyl acetate
solution was washed 3 times with water and dried over magnesium sulfate.
Evaporation of the solvent gave crude ethyl
3-{3,5-difluoro-2-›2-(ethoxycarbonyl)vinyl!phenyl}acrylate (36 g).
Ethyl 3-{3,5-difluoro-2-›2-(ethoxycarbonyl)vinyl!phenyl}acrylate (5.7 g,
18.4 mmol) in 250 mL of ethyl acetate was hydrogenated at 60 psi over 10%
palladium on carbon (0.57 g) for 4 hours and then the mixture was filtered
through Celite. Evaporation of the solvent gave ethyl
3-{3,5-difluoro-2-›2-(ethoxycarbonyl)ethyl!phenyl}propionate (5.73 g, 22.4
mmol) as a colorless oil.
Potassium tert-butoxide (167 mL, 0.167 mol) in DMF was added to 400 mL of
toluene and the DMF was removed by evaporation. Ethyl
3-{3,5-difluoro-2-›2-(ethoxycarbonyl)ethyl!phenyl}propionate (5.65 g, 18.0
nmol) was added and the mixture was stirred under argon at 100.degree. C.
for 8 hours. The mixture was cooled to 0.degree. C., acidified with 11.5
mL of acetic acid, washed 3 times with water and dried over magnesium
sulfate. Evaporation of the solvent gave a mixture of ethyl
1,3-difluoro-6,7,8,9-tetrahydro-7-oxo-5H-benzo-cycloheptene-6-carboxylate
and ethyl
1,3-difluoro-6,7,8,9-tetrahydro-7-oxo-5H-benzocycloheptene-8-carboxylate
(4.3 g).
The carboxylate isomers (4.2 g) were dissolved in 20 mL of acetic acid and
10 mL of 9N hydrochloric acid and the solution was refluxed for 10 hours.
The mixture was cooled to room temperature and extracted with diethyl
ether (1.times.200 mL and then 1.times.50 mL). The extracts were combined
and mixed with 120 mL of 10% aqueous sodium carbonate. The organic layer
was dried over magnesium sulfate and then the solvent was removed by
evaporation. Purification of the residue by flash chromatography (elution:
50% methylene chloride/hexane) gave
1,3-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (1.5 g, 7.6
mmol).
1,3-Difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (1.5 g, 7.6 mmol)
was dissolved in 30 mL of dry THF, the solution was cooled to 0.degree. C.
under argon and 1M LAH (7.5 mL, 7.5 mmol) in THF was added over 2 minutes.
The mixture was stirred at 0.degree. C. for 1 hour and then 0.28 mL of
water, 0.28 mL of 15% aqueous sodium hydroxide and 0.9 mL of water were
added sequentially. The mixture was stirred for 5 minutes, filtered,
washed with ethyl acetate and dried over magnesium sulfate. Evaporation of
the solvents gave
1,3-difluoro-6,7,8,9-tetrahydro-7-hydroxy-5H-benzocycloheptene (1.55 g,
7.8 mmol) as an oil.
EXAMPLE 6
(S)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride
The following is the preparation of a compound of Formula 3 in which n is
1, t is 2 and R.sup.1 is fluoro at the 5- and 7-position.
(a) Trifluoroacetic anhydride (7.7 kg, 5.3 L, 37.5 mol) was heated to
reflux and a solution of L-aspartic acid (2.0 kg, 15.0 mol) in 9 L of
trifluoroacetic acid (prepared by gradually heating to 65.degree. C. and
stirring for 3 hours) was added to the refluxing TFAA over 30 minutes. The
mixture then was distilled and 9 L of TFA was removed. The remaining
mixture was added to 8 L of cold hexane under nitrogen. The hexane mixture
was stirred for 3 hours in an ice bath giving a crystalline material. The
material was isolated by filtration and the filtered residue was washed
with approximately 25 L of hexane. Drying to constant weight in a vacuum
oven at 50.degree. C. under a nitrogen gas bleed gave
N-(trifluoroacetyl)-L-aspartic anhydride (2.9 kg, 13.7 mol), m.p.
140.degree.-141.degree. C. ›.alpha.!.sub.D -27.4.degree. (c=3.28, THF).
(b) A solution of 1,3-difluorobenzene (2.3 kg, 20.0 mol) in 5 L of
methylene chloride was added to a mixture of
N-(trifluoroacetyl)-L-aspartic anhydride (4.2 kg, 20.0 mol) and aluminum
chloride (7.4 kg, 55.5 mol) in 25 L of methylene chloride. The temperature
of the reaction mixture was increased gradually over 1.5 hours and held at
reflux for an additional 3 hours. The mixture then was cooled and 10 L of
water and 20 L of 6N hydrochloric acid were added with good agitation. The
methylene chloride layer was separated, washed with water and then brine,
and the volatiles were removed by distilling at atmospheric pressure.
The residue was dissolved in 40 L of toluene and 8 L of volatiles was
removed by distilling the mixture in vacuo. The solution was heated to
50.degree. C. and 8 L of hexane was added. The mixture was cooled to
30.degree. C. and 90 L of hexane was added. The mixture then was stirred
at 25.degree. C. for 3 hours giving a crystalline material. The material
was isolated by filtration and the filtered residue was washed with hexane
(3.times.10 L). Drying to a constant weight in a vacuum oven at room
temperature under a nitrogen bleed gave
(S)-2-›(trifluoroacetyl)amino!-4-(2,4-difluorophenyl)-4-oxobutanoic acid
(5.2 kg, 16.0 mol), m.p. 82.4.degree.-84.0.degree. C. ›.alpha.!.sub.D
+15.2.degree. (c=0.956, CH.sub.3 OH).
(c) A mixture of
(S)-2-›(trifluoroacetyl)amino!-4-(2,4-difluorophenyl)-4-oxobutanoic acid
(4.8 kg, 14.7 mol) and activated carbon, Darco.RTM., (0.4 kg) in 5 L of
acetic acid was stirred at room temperature for 1 hour. The mixture was
filtered on to Pearlman's catalyst (0.5 kg, 50% wet) and washed in with 15
L of glacial acetic acid. Sulfuric acid (1.2 L, 21.8 mol) in 1 L of
glacial acetic acid was filtered into the mixture and washed in with 2.8 L
of glacial acetic acid. The reaction vessel was vacuum/pressure purged 3
times with nitrogen and then 6 times with hydrogen to 10 psig. The mixture
was stirred vigorously under hydrogen at atmospheric pressure at room
temperature, for 24 hours. The reaction vessel then was purged with
nitrogen and the mixture was filtered onto 4.6 kg of sodium acetate
trihydrate. The filter was washed with 10 L of glacial acetic acid. The
glacial acetic acid was removed by distilling the mixture in vacuo.
The residue was partitioned between 20 L of methylene chloride and 40 L of
water. The aqueous layer was extracted with 10 L of methylene chloride and
the combined methylene chloride was washed with 10 L of water. The
methylene chloride mixture then was dried over sodium sulfate (10 kg) and
filtered. The solvent was removed in vacuo and the residue was dissolved
in 5 L of methylene chloride. The solution was added under nitrogen to 15
L of hexane at a rate such that the temperature of the hexane mixture
remained between 0.degree. and 5.degree. C. The mixture was allowed to
stand for 1 hour giving a crystalline material. The material was isolated
by filtration and the filter residue was washed with 10 L of hexane.
Drying to constant weight in vacuo at 25.degree. C. with a nitrogen bleed
gave (S)-2-›(trifluoroacetyl)amino!-4-(2,4-difluorophenyl)butanoic acid
(3.3 kg, 10.4 mol), m.p. 62.degree.-83.5.degree. C. An analytically pure
sample had a melting point of 86.degree.-89.degree. C. ›.alpha.!.sub.D
+6.8.degree. (c=0.995, CH.sub.3 OH).
(d) A suspension of phosphorus pentachloride (2.2 kg, 10.6 mol) in 12 L of
methylene chloride was cooled to 5.degree. C. and
(S)-4-(2,4-difluorophenyl)-2-›(trifluoroacetyl)amino!butanoic acid (3.1
kg, 9.9 mol) in 12 L of methylene chloride was added over 20 minutes. Thin
layer chromatography of a methanol-quenched aliquot confirmed that the
butanoic acid had converted to the corresponding acid chloride.
The mixture was stirred for 30 minutes and then was added to a slurry of
aluminum chloride (4.3 kg) in 38.8 L of methylene chloride at a rate such
that the temperature of the slurry remained between 1.degree. and
5.degree. C. The reaction mixture was stirred for 1 hour and then added to
28 kg of ice and 5.3 kg of concentrated hydrochloric acid. The mixture was
stirred for 1 hour and the temperature allowed to rise to 20.degree. C.
The aqueous layer was separated and extracted with methylene chloride
(2.times.15 L). The methylene chloride layer was washed once with water
and combined with the methylene chloride extracts. The combined methylene
chloride then was washed with water. The pH of the aqueous phase was
adjusted to 6 by addition of aqueous sodium bicarbonate solution. The
methylene chloride layer was washed with water and then brine. The
methylene chloride was dried over sodium sulfate and filtered. The mixture
was concentrated by evaporation at atmospheric pressure and the residue
was dissolved in 15 L of methanol. The methanol solution was distilled to
9.9 L of methylene chloride and then 9.9 L of water was added. The mixture
was warmed to 56.degree. C., allowed to cool to room temperature and then
stirred for approximately 12 hours. A crystalline material was obtained
and isolated by filtration. The filter residue was washed with 15 L of
water. The isolated material was dried to constant weight in vacuo at roan
temperature with a nitrogen bleed.
The material was dissolved in 5 L of toluene at a temperature of 90.degree.
C. and combined with 10 L of heptane at a temperature of 80.degree. C. The
temperature of the mixture gradually was decreased over 1.5 hours. The
mixture then was stirred at 5.degree. C. for approximately 12 hours giving
a crystalline material. The material was isolated by filtration and the
filter residue was washed with 15 L of heptane. Drying to constant weight
in vacuo at roan temperature with a nitrogen bleed gave
(S)-5,7-difluoro-2-›(trifluoroacetyl)amino!-3,4-dihydro-(2H)-naphthalen-1-
one (2.0 kg, 6.8 mol), m.p. 142.4.degree.-144.6.degree. C. ›.alpha.!.sub.D
-59.4.degree. (c=0.994, CH.sub.3 OH).
(e) A reaction vessel containing a mixture of
(S)-5,7-difluoro-2-›(trifluoroacetyl)amino!-3,4-dihydro-(2H)-naphthalen-1-
one (1.1 kg, 3.8 mol) and Pearlman's catalyst (0.55 kg, 50% wet) in 11 L of
TFA was vacuum/pressure purged 8 times with nitrogen and then 8 times with
hydrogen to 11 psig. The mixture was stirred vigorously under hydrogen
(125 psig) at roan temperature for 24 hours. Thin layer chromatography
confirmed that the naphthalen-1-one had converted to
(S)-1-hydroxy-5,7-difluoro-2-›(trifluoroacetyl)amino!-3,4-dihydro-(2H)-nap
hthalene.
(f) Sulfuric acid (1.1 L, 19.4 mol) in i n of TFA then was added and the
mixture stirred under hydrogen (125 psig) at roan temperature for an
additional 24 hours. The reaction vessel then was purged with nitrogen and
the mixture was filtered over Celite and washed through with 11 L of TFA.
The filtrate was combined with 2.8 kg sodium acetate trihydrate and 80 L
of water. The mixture was cooled to 10.degree. C. giving a crystalline
material. The material was isolated by filtration and the filter residue
was washed with 10 L of ice water. Drying gave
(S)-5,7-difluoro-2-›(trifluoroacetyl)amino!-1,2,3,4-tetrahydronaphthalene
(0.8 kg, 2.9 mol), m.p. 159.9.degree.-160.9.degree. C. ›.alpha.!.sub.D
-56.0.degree. (c=1.01, Ch.sub.3 OH).
(g) Lithium hydroxide monohydrate (7.8 g, 0.2 mol) was added to a solution
of
(S)-5,7-difluoro-2-›(trifluoroacetyl)amino!-1,2,3,4-tetrahydronaphthalene
(20.8 g, 74.5 mmol) in 187 mL of methanol and 21 mL of water. The mixture
was stirred at reflux for 30 minutes and diluted with 200 mL of methanol.
The diluted mixture then was combined with 60 mL of water, 24.8 mL of
concentrated hydrochloric acid and 4.2 g of activated carbon, Darco.RTM..
The mixture was stirred for 30 minutes and then filtered through Celite.
The filtrate was distilled until the head temperature reached 75.degree.
C. The remaining mixture was allowed to cool and let stand for
approximately 60 hours. The mixture then was cooled in an ice bath giving
a crystalline material. The material was isolated by filtration and the
filter residue was washed with water. Drying to constant weight in vacuo
at room temperature under a nitrogen stream gave
(S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride
(14.8 g, 67.6 mol), m.p.>280.degree. C. ›.alpha.!.sub.D -66.2.degree.
(c=0.162, CH.sub.3 OH).
EXAMPLE 7
(R)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalan-2-yl methanesulfonate
The following is the preparation of a compound of Formula 5 in which n is
1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and L is mesyloxy.
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (59.0
g, 0.32 mol), prepared as in Example 3, and triethylamine (13.8M, 74.2 mL,
0.53 mol) in 1.78 L of diethyl ether was cooled using a methanol/ice bath.
Methanesulfonyl chloride (12.9M, 37.2 mL, 0.48 mol) was added under argon
over 5-10 minutes and the mixture was stirred at room temperature for 18
hours. The mixture was partitioned between water and ether and the ether
layer was separated and the aqueous layer was extracted with ether. The
combined ether layers were washed once with each of 1N hydrochloric acid,
saturated sodium bicarbonate solution and brine and then dried over
magnesium sulfate. Evaporation gave crude
(R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate as an
off-white solid (87.12 g), m.p. 79.degree.-80.degree. C.
›.alpha.!.sub.D.sup.25 =+16.77.degree. (c=2.0, CHCl.sub.3).
Proceeding as in Example 7 but substituting different starting materials
for (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene, the
following compounds of Formula 5 were made:
substituting 1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (R)-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(R)-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (R)-5-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(S)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (R)-6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(S)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (R)-7-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(S)-7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting 6,7-dichloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
2-6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (-)-6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting 6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (S)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting 5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting 6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting (R)-6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene gave
(S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate;
substituting 6,8-difluoro-1,2,3,4-tetrahydro-2-hydroxy-7-methoxynaphthalene
gave 6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl
methanesulfonate;
substituting 2-hydroxyindane gave indan-2-yl methanesulfonate;
substituting 4,6-difluoro-2-hydroxyindane gave 4,6-difluoroindan-2-yl
methanesulfonate;
substituting 5,6-difluoro-2-hydroxyindane gave 5,6-difluoroindan -2-yl
methanesulfonate;
substituting 5,6-difluoro-1-hydroxyindane gave 5,6-difluoroindan-1-yl
methanesulfonate; and
substituting 5,7-difluoro-1-hydroxyindane gave 5,7-difluoroindan-1-yl
methanesulfonate.
EXAMPLE 8
(S)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride
The following is the preparation of a compound of Formula 3 in which n is
1, t is 2 and R.sup.1 is fluoro at the 5- and 7-position.
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate (54.0 g), prepared as in Example 7, and lithium azide
(15.8 g, 0.322 mol) in 400 mL of DMF was stirred under argon at 50.degree.
C. for 16 hours. The reaction was quenched with 200 mL of water and the
mixture extracted with 1 L of pentane. The extract was washed with 50 mL
of water and dried over magnesium sulfate. Evaporation under reduced
pressure at 35.degree. C. gave crude
(S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene as a yellow oil
residue (59.8 g).
The azide residue was dissolved in 1.2 L of ethyl acetate and hydrogenated
over 10% palladium on carbon (6 g) for 6 hours, recharging with hydrogen
every hour to remove evolved nitrogen gas. The mixture was then filtered
through Celite and stirred with ethereal hydrogen chloride (1N, 250 mL)
giving a crystalline material. The material was isolated by filtering.
over 4 hours and the filter residue was washed with ethyl acetate.
Removing the remaining solvents in vacuo gave
(S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride
(48.2 g, 0.22 mol) as a white solid, m.p.>280.degree. C.
›.dbd.!.sub.D.sup.25 =-60.15.degree. (c=2.7, CH.sub.3 OH).
Proceeding as in Example 8 but substituting a different starting material
for (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate,
the following compounds of Formula 3 were made:
substituting 1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate gave
1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride, m.p.
239.degree.-242.degree. C.;
substituting (R)-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate gave
(S)-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride, m.p.
241.degree.-244.degree. C.;
substituting (R)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave (S)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride, m.p.>280.degree. C.;
substituting (R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave (S)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride, m.p. 264.degree.-265.degree. C.;
substituting (R)-7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave (S)-7-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride, m.p.>280.degree. C.;
substituting 6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride, m.p.>280.degree. C.;
substituting (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave
(-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride;
substituting 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride;
substituting (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave
(R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride,
m.p.>280.degree. C.;
substituting 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride;
substituting 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride;
substituting (R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
methanesulfonate gave
(S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride;
substituting 6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl
methanesulfonate gave
6,8-difluoro-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride;
substituting 2-indan-2-yl methanesulfonate gave indan-2-ylamine
hydrochloride;
substituting 4,6-difluoroindan-2-yl methanesulfonate gave
4,6-difluoroindan-2-ylamine;
substituting 5,6-difluoroindan-2-yl methanesulfonate gave
5,6-difluoroindan-2-ylamine hydrochloride, m.p.>280.degree. C.;
substituting 5,6-difluoroindan-1-yl methanesulfonate gave
5,6-difluoroindan-1-ylamine hydrochloride; and
substituting 5,7-difluoroindan-1-yl methanesulfonate gave
5,7-difluoroindan-1-ylamine hydrochloride.
EXAMPLE 9
5,7-difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-t
hione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2 and R.sup.3, R.sup.4 and R.sup.5 are each hydro and R.sup.1
fluoro at the 5- and 7-position.
A mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.05
g, 11.2 mmol), prepared as in Example 8, and dimethoxyacetaldehyde (1.73
g, 13.1 mmol) in 50 mL of ethanol was hydrogenated over 10% palladium on
carbon (500 mg) for 18 hours. The mixture was filtered and concentrated by
evaporation. The residue was combined with potassium thiocyanate (1.57 g,
16.2 mmol) in 30 mL of 1N hydrochloric acid and 20 mL of ethanol and the
mixture was heated at 70.degree.-80.degree. C. for 18 hours. The mixture
was cooled in an ice bath giving a crystalline material which was isolated
by filtration. Recrystallization from ethyl acetate/hexane gave
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione (1.27 g, 4.76 mmol), m.p. 250.degree.-251.degree. C.
Proceeding as in Example 9 but substituting a different starting material
for (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine, the following
compounds of Formula I were made:
substituting 7-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole
-2-thione, m.p. 215.degree.-217.degree. C.;
substituting 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione, m.p. 242.degree.-243.degree. C.;
substituting 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione, m.p. 260.degree.-261.degree. C.;
substituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(1,2,3,4-tetrahydro-5-methoxynaphthalen-2-yl)-1,3-dihydroimidazole
-2-thione, m.p. 233.degree.-235.degree. C.;
substituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(1,2,3,4-tetrahydro-6-methoxynaphthalen-2-yl)-1,3-dihydroimidazole
-2-thione, m.p. 226.degree.-227.degree. C.;
substituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 271.degree.-273.degree. C.;
substituting 8-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
1-(1,2,3,4-tetrahydro-8-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 249.degree.-251.degree. C.;
substituting 6,8-difluoro-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylamine
gave
1-(6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl)-1,3-dihydroim
idazole-2-thione, m.p. 228.degree.-230.degree. C.;
substituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine gave
1-(1,2,3,4-tetrahydro-5-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 176.degree.-177.degree. C.;
substituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine gave
1-(1,2,3,4-tetrahydro-6-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 190.degree.-192.degree. C.;
substituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylamine gave
1-(1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 142.degree.-143.degree. C.;
substituting 4,6-difluoroindan-2-ylamine gave
1-(4,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione, m.p.
185.degree.-186.degree. C.;
substituting 5,6-difluoroindan-2-ylamine gave
1-(5,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione, m.p.
255.degree.-257.degree. C.;
substituting 5-methoxyindan-1-ylamine gave
1-(5-methoxyindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
195.degree.-196.degree. C.;
substituting (-)-4,6-difluoroindan-1-ylamine gave
(+)-1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
191.degree.-193.degree. C.;
substituting (+)-4,6-difluoroindan-1-ylamine gave
(-)-1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
181.degree.-191.degree. C.;
substituting 5,6-difluoroindan-1-ylamine gave
1-(5,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
183.degree.-187.degree. C.; and
substituting 5,7-difluoroindan-1-ylamine gave
1-(5,7-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
212.degree.-215.degree. C.
EXAMPLE 10
(-)-6,7-Difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene
The following is the preparation of a compound of Formula 9 in which n is
1, t is 2 and R.sup.1 is fluoro at the 6- and 7-position.
A mixture of (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56
g, 3.06 mmol), prepared as in Example 8, and 1,1'-thiocarbonyldiimidazole
(0.82 g, 4.59 mmol) in 15 mL of ethyl acetate was stirred until the
reaction was complete. The solvent was removed by evaporation.
Purification of the residue by column chromatography on silica gel
(solution: 5% acetone/methylene chloride) gave
(-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.55 g,
2.42 mmol). ›.alpha.!.sub.D.sup.25 -15.5.degree. (c=1.0, CH.sub.3 OH)
Proceeding as in Example 10ut substituting a different starting material
for (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine, the following
compounds of Formula 9 were made:
substituting 1,2,3,4-tetrahydronaphthalen-2-ylamine gave
2-isothiocyano-1,2,3,4-tetrahydronaphthalene as an oil; and
substituting (+)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(+)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene, m.p.
206-207.
EXAMPLE 11
(-)-6,7-Difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole
-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2 and R.sup.3, R.sup.4 and R.sup.5 are each hydro and R.sup.1
is fluoro at the 6- and 7-position.
A mixture of (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene
(0.49 g, 2.2 mmol), prepared as in Example 10, and 2,2-dimethoxyethylamine
(0.23 g, 2.2 mmol) in DMF was heated at 85.degree. C. under argon for 2.5
hours. The solvent was removed under reduced pressure and the residue was
dissolved in 2 to 3 mL of ethanol and 20 mL of 4N hydrochloric acid. The
solution was heated at 85.degree. C. for approximately 48 hours and cooled
giving a crystalline material. The material was isolated by filtration and
dried. Purification by column chromatography on silica gel (elution: 3%
methanol/methylene chloride) gave
(-)-6,7-difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazol
e-2-thione (0.225 g, 0.84 mmol), m.p. 200.degree.-205.degree. C.
›.alpha.!.sub.D.sup.25 -77.9.degree., (c=0.6, 2:1 CHCl.sub.3 /CH.sub.3
OH).
Proceeding as in Example 11 but substituting
(+)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene for
(+)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene gave
(+)-6,7-difluoro-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazol
e-2-thione (0.225 g, 0.84 mmol), m.p. 206.degree.-207.degree. C.
›.alpha.!.sub.D.sup.25 86.98.degree., (c=1.06, 2:1 CHCl.sub.3 /CH.sub.3
OH).
EXAMPLE 12
1-(4,6-Difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 0, t is 2, R.sup.1 is fluoro at the 4- and 6-position and R.sup.3,
R.sup.4 and R.sup.5 are each hydro.
A mixture of 4,6-difluoroindan-1-one (11.3 g, 67.26 mmol),
2,2-dimethoxyethylamine (7.07 g, 67.26 mmol) and sodium cyanoborohydride
(4.23 g) in 75 mL of methanol was heated at gentle reflux and stirred
under nitrogen for approximately 18 hours. Additional sodium
cyanoborohydride (2.12 g) was added and the mixture was heated at
65.degree. C. for 20 hours. The solvents were removed by evaporation.
Purification of the residue by column chromatography on silica gel
(elution: 2.5% methanol/methylene chloride) gave
(4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine.
A mixture of (4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine (11.68 g,
45.9 mmol), potassium thiocyanate (4.46 g, 45.9 mmol) in 21.6 mL of 12N
hydrochloric acid, 86 mL of ethanol and 86 mL of water was heated at
80.degree. to 85.degree. C. for 15 hours. The mixture was cooled in an ice
bath and diluted with water giving a crystalline material. The material
was isolated by filtration and the filter residue was rinsed with cold
ethanol (2.times.25 mL) and 50 mL of diethyl ether. Drying gave
1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione (5.65 g, 22.2
mmol), m.p. 205.degree.-207.degree. C.
Proceeding as in Example 12 but substituting a different starting material
for 4,6-difluoroindan-1-one, the following compounds of Formula I were
made:
substituting 1,2,3,4-tetrahydronaphthalen-1-one gave
1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
188.degree.-189.degree. C.;
substituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one gave
1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 190.degree.-192.degree. C.;
substituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-one gave
1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 176.degree.-177.degree. C.;
substituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-one gave
1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 142.degree.-143.degree. C.;
substituting indan-2-one gave 1-(indan-2-yl)-1,3-dihydroimidazole-2-thione,
m.p. 210.degree.-211.degree. C.; and
substituting indan-1-one gave 1-(indan-1-yl)-1,3-dihydroimidazole-2-thione,
m.p. 136.degree.-137.degree. C.
EXAMPLE 13
1-(1,2,3,4-Tetrahydronaphthalen-2-yl)imidazole
The following is the preparation of a compound of Formula 11 in which n is
1 and t is 0.
A mixture of 1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (15.74 g,
69.6 mmol), prepared as in Example 7, and imidazole (23.68 g, 349 mmol) in
100 mL of DMF was heated at 80.degree. to 90.degree. C. under argon for 24
hours. The solvent was removed under vacuum by rotary evaporation. The
residue was dissolved in 500 mL of ethyl acetate and the solution was
washed with water (5.times.250 mL). The combined aqueous layer was
extracted with 500 mL of ethyl acetate and the extract was then washed
with water (5.times.250 mL). The combined ethyl acetate extract was washed
with saturated sodium chloride solution, dried over magnesium sulfate and
concentrated by rotary evaporation. Purification of the residue by column
chromatography on silica gel (elution: 5% methanol/methylene chloride)
gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole (5.18 g, 26.1 mol),
m.p. 93.degree.-95.degree. C.
Proceeding as in Example 13, but substituting 4-methylimidazole for
imidazole and 2-bromo-1,2,3,4-tetranaphthalen-1-one for
1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate and then reducing gave
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-methylimidazole.
EXAMPLE 14
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-im
idazol-4-ylmethyl!formamide
The following is the preparation of a compound of Formula 11 in which n is
1, t is 2, R.sup.1 is fluoro at the 5- and 7-positions and R.sup.4 is
hydro.
A mixture of formamide, prepared as in Example 29,
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide (1.38 g, 4.27 mmol) and activated
Raney.RTM. nickel (11 g) in 50 mL of ethanol was stirred rapidly at
80.degree. C. for 1 hour. The mixture was filtered through Celite and the
filtrate evaporated to give a white solid (0.98 g). The solid was
recrystallized from ethyl acetate/methanol to give
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-i
midazol-4-ylmethyl!formamide, m.p. 194.degree.-195.degree. C.
Proceeding as in Example 14, but substituting a different starting material
for
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide gave the following compounds of
Formula 11:
substituting
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride gave
(S)-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-imi
dazol-4-ylmethyl!amine, m.p. 273.degree.-274.degree. C.; and
substituting
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione gave
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole.
EXAMPLE 15
3-Amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is amino and R.sup.4 and R.sup.5 are each hydro.
A mixture of 1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole (198 mg, 1
mmol), prepared as in Example 13, and O-mesitylenesulfonylhydroxylamine
(215 mg, 1 mmol) in acetonitrile was stirred under argon for 18 hours. The
reaction mixture was diluted with diethyl ether giving a precipitate as an
oil. The solvents were decanted away and the residue was washed with
diethyl ether (2.times.10 mL). Residual solvent was evaporated under
vacuum. A mixture of the residue and lac sulfur (32 mg, 1.0 mmol) in 1 mL
of pyridine and 0.5 mL of triethylamine were heated at approximately
90.degree. C. under argon for 4 hours. The solvent was removed by
evaporation and the residue was co-evaporated with toluene. The residue
was purified by column chromatography on silica gel eluting with methylene
chloride to give
3-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thion
e (5.18 g, 26.1 mmol), m.p. 187.degree.-189.degree. C.
Proceeding as in Example 15, but substituting different starting materials
for O-mesitylenesulfonatehydroxylamine and/or
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave the following
compounds of Formula I:
substituting tert-butyl bromoacetate gave
tert-butyl-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imi
dazol-1-ylacetate, m.p. 167.degree.-169.degree. C.;
substituting methyl 4-bromobutyrate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave methyl
4-›3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol
-1-yl!butyrate;
substituting methyl 5-bromomethylpicolinate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave methyl
5-›3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol
-1-ylmethyl!picolinate as an oil;
substituting methyl 4-bromomethylbenzoate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoate, m.p. 133.degree.-135.degree. C.;
substituting methyl 3-bromomethylbenzoate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave methyl
3-›3-(1,2,3,4-tetrahyfromaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoate, m.p. 130.degree.-132.degree. C.;
substituting 3,4-dimethoxybenzyl chloride and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
3-(3,4-dimethoxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroi
midazole-2-thione, m.p. 129.degree.-131.degree. C.;
substituting methyl 4-bromomethylbenzoate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-methylimidazole gave methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-ylmethyl!benzoate, m.p. 140.degree.-141.degree. C.;
substituting 6-dimethylamino-3-bromopyridazine and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
3-(6-dimethylaminopyridazin-3-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,
3-dihydroimidazole-2-thione, m.p. 198.degree.-199.degree. C.;
substituting 2-bromoethylbenzene and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-imidazole gave
3-(2-phenylethyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazo
le-2-thione, m.p. 140.degree.-142.degree. C.;
substituting methyl 4-(2-bromoethyl)benzoate and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave methyl
4-{2-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidaz
ol-1-yl!ethyl}benzoate, m.p. 159.degree.-161.degree. C.;
substituting 4-(2-bromoethyl)benzoic acid and
1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylethyl!benzoic acid, m.p. 227-230;
substituting 3,4-dimethoxy-1-(2-bromoethyl)benzene and
1-(1,2,3,4-tetrahydronaphthalen-2-yl) imidazole gave
3-›2-(3,4-dimethoxyphenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione, m.p. 97.degree.-101.degree. C.;
substituting 4-(2-bromoethyl)benzoic acid and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
(S)-4-{2-›3-(5,7-difluoro-1,2,34-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-d
ihydro-1H-imidazol-1-yl!ethyl}benzoic acid, m.p. 222.degree.-224.degree.
C., and treating with potassium hydroxide in methanol evaporating to
dryness and recrystallizing from methanol/isopropanol gave potassium
(S)-4-{2-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-
dihydro-1H-imidazol-1-yl!ethyl}benzoate, m.p.>280.degree. C.;
substituting 4-(2-bromoethyl)-1-cyanobenzene and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
(S)-3-›2-(4-cyanophenyl)ethyl!-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthale
n-2-yl)-1,3-dihydroimidazole-2-thione, m.p. 130.degree.-133.degree. C.;
substituting 4-(2-bromoethyl)benzene and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)imidazole gave
(S)-3-(2-phenylethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1
,3-dihydroimidazole-2-thione, m.p. 131.degree.-133.degree. C.;
substituting 4-(2-bromoethyl)-1-cyanobenzene and
1-(1,2,3,4-tetrahydronaphthalen-2-yl) imidazole gave
3-›2-(4-cyanophenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione, m.p. 169.degree.-170.degree. C.;
substituting 4-(2-bromoethyl)benzoic acid and
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-i
midazol-4-ylmethyl!formamide gave
(S)-4-{2-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen
-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!ethyl}benzoic acid; and
substituting ethyl 3-bromopropionate and
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,3-dihydro-1H-i
midazol-4-ylmethyl!formamide gave ethyl
(S)-3-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!propionate.
EXAMPLE 16
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0 and R.sup.3, R.sup.4 and R.sup.5 are each hydro.
A solution of 1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole (1.6 g, 8.1
mmol), prepared as in Example 13, in 30 mL of THF was cooled to
-78.degree. C. and n-butyllithium (6 mL, 9.7 mmol) was added over 15
minutes. The mixture was stirred at -78.degree. C. for 1 hour and lac
sulfur (0.34 g, 10.5 mmol) was added. The mixture was stirred at
-78.degree. C. for an additional 2 hours and then allowed to warm to room
temperature. The mixture was poured into 100 mL of water giving a
crystalline material. The material was isolated by filtration, washed with
ethyl ether and dried. The filtrate was extracted with methylene chloride
(2.times.100 mL) and the extracts were washed with brine, dried over
sodium sulfate and concentrated by evaporation. The residue was purified
by column chromatography on silica gel ›elution: 1.5% methanol (containing
2% concentrated ammonium hydroxide)!. Combining the crystalline material
gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione
(0.81 g, 3.5 mmol), m.p. 233.degree.-234.degree. C.
EXAMPLE 17
5-Amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 and R.sup.4 are hydro and R.sup.5 is amino.
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.92 g, 10.1
mol), prepared as in Example 10, and aminoacetonitrile hydrochloride (0.94
g, 10.1 mmol) in 1.41 mL of triethylamine was heated at 60.degree. C. for
1 hour. The solvent was evaporated and the residue was purified by flash
chromatography (elution: methylene chloride followed by 3% methanol in
methylene chloride). The purified residue was recrystallized from ethyl
acetate/hexane. The residue (1.06 g) and 44 mL of 0.1N potassium hydroxide
was stirred under nitrogen for 15 minutes. The residue was isolated by
filtration, washed with water, air dried and then stirred with methylene
chloride. Filtration and drying gave
5-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thion
e, m.p. 169.degree.-171.degree. C.
EXAMPLE 18
(S)-5-Hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-
dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
hydroxymethyl.
Potassium thiocyanate (15.9 g, 162.6 mmol) was dried by heating to
175.degree. C. under nitrogen and then cooled to 35.degree. C. under
vacuum with several nitrogen purges. A mixture of dihydroxyacetone (15.9
g, 176.7 mmol) and (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride (30.0 g, 137.0 mmol), prepared as in Example 6, in 540 mL of
ethyl acetate was added to the dry potassium thiocyanate. The reaction
vessel was purged with nitrogen and 40.83 g of glacial acetic acid was
added. The reaction mixture was stirred at 35.degree. C. for 2 hours and
100 mL of 1.0M sulfuric acid was added. The mixture was stirred for 15
minutes, then cooled in an ice bath and 2.5M sodium hydroxide was added
until the mixture was pH 7. The organic layer was washed with 50 mL of
saturated aqueous sodium bicarbonate and then 50 mL of brine. The organic
layer was concentrated to 480 mL by distillation and the mixture was
cooled to 6.degree. C. and allowed to stand for 12 hours giving a
crystalline material. The material was isolated by filtration, the filter
residue was washed with cold ethyl acetate and the isolated material
dried.
The material was dissolved in 650 mL of ethyl acetate and 25 mL of water.
The mixture was distilled until 500 mL of volatile were removed. The
mixture was cooled to room temperature and stirred for 45 minutes giving a
crystalline material. The material was isolated by filtration and the
filter residue was washed with cold ethyl acetate. Drying in vacuo with a
nitrogen bleed gave
(S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione (30.4 g, 107.4 mol), m.p.
206.degree.-207.degree. C. ›.alpha.!.sub.D -40.degree. (c=0.682, CH.sub.3
OH).
Proceeding similarly as in Example 18, but substituting
(S)-6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride for
(S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride gave
(S)-5-hydroxymethyl-1-(6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione, m.p. 247.degree.-248.degree. C.
EXAMPLE 19
(S)-5-Cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroi
midazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position, R.sup.3 and
R.sup.4 are each hydro and R.sup.5 is cyano.
A solution of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine
hydrochloride (50.3 g, 0.23 mol), prepared as in Example 8, and sodium
hydroxide (10.0 g, 0.25 mol) in 450 mL of water was heated to 50.degree.
C. and then formaldehyde sodium bisulfite complex (30.8 g, 0.23 mol) was
added. The mixture was stirred for 30 minutes and potassium cyanide (15.0
g, 0.23 mol) was added. The mixture was heated to 80.degree. C., stirred
for 1 hour, cooled to room temperature, and then extracted with ethyl
acetate. Evaporation gave an oily residue (51.3 g). Purification by column
chromatography on silica gel (elution: 5% methanol/methylene chloride)
gave (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino)acetonitrile
(39.4 g) and (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (7.12
g). Proceeding similarly as above, recycling the recovered starting
material and combining yields gave
(S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl-amino)acetonitrile
(44.8 g, 0.20 mol), m.p. 73.degree.-76.degree. C. ›.alpha.!.sub.D.sup.25
=-58.04.degree. (c=1.6, CHCl.sub.3).
A solution of the
(S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino)acetonitrile in
butyl formate (8.7M, 240 mL, 2.10 mol) was heated to reflux and stirred
under nitrogen for 19 hours. The solvents were removed under reduced
pressure, toluene was added and then evaporated. Drying gave
(S)-N-(cyanomethyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)form
amide as an oily residue (53.2 g). A stirring mixture of the formamide
(53.2 g) and ethyl formate (12.4M, 48.7 mL, 0.604 mol) in 0.925 L of
anhydrous THF was cooled to -15.degree. C. A solution of potassium
tert-butoxide in THF (1.0M, 302 mL, 0.302 mol) was added over 20 minutes
and the mixture was stirred for 18 hours. Evaporation of the solvent gave
potassium
(S)-N-(1-cyano-2-oxyvinyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)formamide as a residue.
A mixture of the potassium
(S)-N-(1-cyano-2-oxyvinyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)formamide and potassium thiocyanate (78.1 g, 0.80 mol) in 0.99 L of 1N
hydrochloric acid and 0.497 L of ethanol was heated to 85.degree. C. and
stirred for 135 minutes. The mixture was then cooled in an ice bath to
form a precipitate which was collected as a slurry. Purification by column
chromatography on silica gel packed in hexane (elution: 10%
acetone/methylene chloride) gave
(S)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione (18.1 g, 0.06 mol), m.p. 241.degree.-249.degree. C.
›.alpha.!.sub.D.sup.25 =-69.1.degree. (c=1.20, DMSO).
Proceeding as in Example 19, but substituting a different starting material
for (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride
gave the following compounds of Formula I:
substituting 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione, m.p. 255.degree. C. (dec);
substituting (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(R)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione;
substituting (S)-7-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(S)-5-cyano-1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione;
substituting (S)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(S)-5-cyano-1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione;
substituting (S)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(S)-5-cyano-1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione;
substituting (S)-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(S)-5-cyano-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-t
hione;
substituting 6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
5-cyano-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione;
substituting (S)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
(S)-5-cyano-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione; and
substituting 5,6-difluoroindan-2-ylamine gave
5-cyano-1-(5,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione.
EXAMPLE 20
(S)-5-Aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-di
hydroimidazole-2-thioxo Hydrochloride
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position, R.sup.3 and
R.sup.4 are hydro and R.sup.5 is aminomethyl.
A solution of
(S)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione (5.0 g, 0.017 mol), prepared as in Example 19, in 75 mL
of THF was stirred under argon in an ice bath and a solution of LAH in THF
(1.0M, 34.3 mL, 34.3 mmol) was added dropwise over 10 minutes. The mixture
was cooled to 0.degree. C., stirred for 30 minutes, allowed to warm to
room temperature, and let stand for 1.5 hours. The mixture was cooled to
0.degree. C. and then a sufficient amount of saturated sodium potassium
tartrate solution was added such that the mixture could by freely stirred.
An additional 30 mL of saturated sodium potassium tartrate solution and
200 mL of 10% methanol in methylene chloride were added, the mixture was
stirred for 15 minutes, and then 100-150 mL of water was added. The
organic layer was separated and the aqueous phase was extracted twice with
10% methanol in methylene chloride (2.times.125 mL). The combined extracts
were washed with 75 mL of water, dried over magnesium sulfate, and
concentrated by evaporation to a residue (5.2 g). Purification by column
chromatography on silica gel (elution: 5% methanol/methylene chloride)
gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-
1,3-dihydroimidazole-2-thione (2.92 g, 10.0 mmol).
The
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione was dissolved in methanol and treated with 1.5
equivalents of anhydrous hydrogen chloride in ethyl ether. Removal of the
solvents by co-evaporation with ethyl acetate gave
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride, m.p. 245.degree. C.,
›a.alpha.!.sub.D.sup.25 =11.30.degree. (c=0.5, DMSO).
Proceeding as in Example 20, but substituting a different starting material
for
(S)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione gave the following compounds of Formula I:
substituting
5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione, m.p. 172.degree.-178.degree. C. and
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione hydrochloride, m.p. 265.degree.-270.degree. C.;
substituting
(R)-5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione gave
(R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride;
substituting
(S)-5-cyano-1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
(S)-5-aminomethyl-1-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione hydrochloride, m.p. 237.degree.-247.degree. C.;
substituting
(S)-5-cyano-1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
(S)-5-aminomethyl-1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione hydrochloride, m.p. 240.degree.-249.degree. C.;
substituting
(S)-5-cyano-1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
(S)-5-aminomethyl-1-(5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione hydrochloride, m.p. 273.degree.-276.degree. C.;
substituting
(S)-5-cyano-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-t
hione gave
(S)-5-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazo
le-2-thione hydrochloride, m.p. 255.degree.-258.degree. C.;
substituting
5-cyano-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
5-aminomethyl-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione hydrochloride, m.p. 260.degree.-263.degree. C. (dec);
substituting
(S)-5-cyano-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro
imidazole-2-thione gave
(S)-5-aminomethyl-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride, m.p. 253.degree.-270.degree. C.;
and
substituting
5-cyano-1-(5,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione gave
5-aminomethyl-1-(5,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione
hydrochloride, m.p. >280.degree. C. (dec).
EXAMPLE 21
1-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5(1H)-tetrazol-5-yl-1,3-
dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
1H-tetrazol-5-yl.
A mixture of
5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione (0.554 g, 1.9 mmol), prepared as in Example 19, in 1.6 mL of
tributyltin azide was heated at 130.degree. C. under a nitrogen atmosphere
for 2.5 hours and then 10 mL of toluene was added. The mixture was allowed
to cool to room temperature and approximately 5 mL of diethyl ether was
added. The mixture was cooled to 0.degree. C. and then treated with 10 mL
of 1N hydrogen chloride in diethyl ether for approximately 15 minutes. The
mixture was poured into a solution of potassium fluoride monohydrate (15.0
g) in 15 to 20 mL of water and 75 mL of ethyl acetate. The ethyl acetate
layer was extracted with 2N sodium hydroxide and the aqueous layer was
washed 6 times with methylene chloride. The aqueous layer was acidified
with concentrated hydrochloric acid and then extracted with ethyl acetate.
Evaporation of the solvents gave
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5(1H)-tetrazol-5-yl-1,3
-dihydroimidazole-2-thione (0.57 g, 1.7 mmol), m.p. 214.degree.-215.degree.
C.
Proceeding as in Example 21, but substituting a different starting material
for
5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave the following compounds of Formula I:
substituting
5-cyano-1-(5,6-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione gave
1-(5,6-difluoroindan-2-yl)-5(1H)-tetrazol-5-yl-1,3-dihydroimidazole-2-thio
ne, m.p. 142.degree.-147.degree. C.; and
substituting
5-cyano-1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimid
azole-2-thione gave
1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5(1H)-tetrazol-5-yl-1,3
-dihydroimidazole-2-thione, m.p. 195.degree.-212.degree. C.
EXAMPLE 22
3-(1,2,3,4-Tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-c
arbaldehyde
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 and R.sup.5 are each hydro and R.sup.4 is formyl.
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.89 g, 10
mmol), prepared as in Example 10, and D-(+)-glucosamine (1.78 g, 10 mmol)
was stirred at 90.degree. C. until homogenous and then 0.8 mL of acetic
acid was added. The mixture was stirred at 90.degree. C. for 30 minutes
and then cooled. The solvents were removed by rotary evaporation and the
residue was co-evaporated with toluene (2.times.25 mL). The residue was
dissolved in acetic acid and heated at 90.degree. to 100.degree. C. for 30
minutes. The mixture was cooled and triturated with acetone giving a
crystalline material. The material was isolated by filtration and the
filter residue washed with acetone. Drying gave
4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)
-1,3-dihydroimidazole-2-thione (1.48 g, 4.23 mmol).
A suspension of
4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)
-1,3-dihydroimidazole-2-thione (0.252 g, 0.72 mmol) and lead tetraacetate
(0.851 g, 1.92 mmol) in 15 mL of 33% acetic acid/benzene was stirred until
the mixture was homogenous and 30 minutes. The reaction mixture was poured
into 125 mL of saturated sodium carbonate solution and the mixture was
filtered. The organic layer was separated, dried over magnesium sulfate
and concentrated. The residue was dissolved in 40 mL of THF and 2 mL of
sulfurous acid (6% SO.sub.2). Evaporation of the solvent gave
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-
carbaldehyde (0.15 g, 0.59 mmol), m.p. 206.degree.-210.degree. C.
Proceeding as in Example 22, but substituting
(S)-2-isothiocyano-5,7-difluoro-1,2,3,4-tetrahydronaphthalene for
2-isothiocyano-1,2,3,4-tetrahydronaphthalene gave
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazole-5-carbaldehyde, m.p. >285.degree. C.
EXAMPLE 23
Ethyl›(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetate
The following is the preparation of a compound of Formula 17 in which n is
1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.32 is
ethoxycarbonyl.
A mixture of 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (6.0 g,
32.8 mmol), prepared as in Example 8, and ethyl glyoxylate (4.6 g, 36.0
mmol) in 300 mL of ethanol was hydrogenated over 10% palladium on carbon
(0.75 g) for 10 hours. The mixture was filtered and concentrated by
evaporation. Purification of the residue by column chromatography on
silica gel (elution: 30% ethyl acetate/hexane) gave
ethyl›(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino!acetate (7.5
g, 27.9 mmol) as an oil.
A solution of
ethyl›(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-amino!acetate (7.15
g, 25.6 mmol) in 20 mL of methylene chloride under argon was cooled to
approximately 0.degree. C. Acetic formic anhydride (9.7 mL, 67.3 mmol) was
cooled to 0.degree. C. and added over 5 to 10 minutes. The mixture was
stirred 0.degree. C. for 2 hours and then allowed to warm to room
temperature. The solvent was removed by co-evaporation with toluene
(3.times.50 mL). Crystallization of the residue under high vacuum gave
ethyl›(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetat
e (7.68 g, 25.0 mmol).
Proceeding as in Example 23, but substituting a different starting material
for 5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave the following
compounds of Formula 17:
substituting 6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine gave
ethyl›(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetat
e;
substituting 4,6-difluoroindan-2-ylamine gave
ethyl›(4,6-difluoroindan-2-yl)(formyl)amino!acetate;
substituting 5,7-difluoroindan-2-ylamine gave
ethyl›(5,7-difluoroindan-2-yl)(formyl)amino!acetate; and
substituting 5,6-difluoroindan-2-ylamine gave
ethyl›(5,6-difluoroindan-2-yl)(formyl)amino!acetate.
EXAMPLE 24
Ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.1 is fluoro at the 5- and 7-position, R.sup.3 and
R.sup.4 are hydro and R.sup.5 is ethoxycarbonyl.
A mixture of
ethyl›(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetat
e (7.58 g, 24.7 mmol), prepared as in Example 23, and ethyl formate (5.91
mL, 72.7 mmol) in 60 mL of THF was cooled to -10.degree. C. under argon.
Potassium tert-butoxide (4.08 g, 36.4 mmol) in 45 mL of THF was added and
the mixture was stirred at -10.degree. C. for 2 hours. The mixture then
was allowed to warm to room temperature and stirred for an additional 4
hours. The solvent was removed by evaporation and the residue was
dissolved in 75 mL of 1N hydrochloric acid and 50 mL of ethanol. Potassium
thiocyanate (2.65 g, 75 mmol) was added and the mixture was stirred at
85.degree. C. for 15 hours. The mixture was cooled, diluted with 125 mL of
water and extracted with ethyl acetate. The extract was dried over
magnesium sulfate and the ethyl acetate was removed by rotary evaporation.
Purification of the residue by column chromatography on silica gel
(elution: 2.5% methanol/methylene chloride) gave ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate (8.07 g, 24.6 mmol), m.p. 159.degree.-161.degree.
C.
Proceeding as in Example 24, but substituting a different starting material
for
ethyl›(5,7-difluoro-1,1,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetat
e gave the following compounds of Formula I:
substituting
ethyl›(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetat
e gave ethyl
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate, m.p. 187.degree.-189.degree. C.;
substituting ethyl(1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)aminoacetate
gave ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-
carboxylate, m.p. 70-72;
substituting
ethyl(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)aminoacetate gave
ethyl
3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imi
dazole-4-carboxylate;
substituting ethyl›(4,6-difluoroindan-2-yl)(formyl)amino!acetate gave ethyl
3-(4,6-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
gave;
substituting ethyl›(5,7-difluoroindan-2-yl)(formyl)amino!acetate gave ethyl
3-(5,7-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
; and
substituting ethyl›(5,6-difluoroindan-2-yl)(formyl)amino!acetate gave ethyl
3-(5,6-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
.
EXAMPLE 25
Ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl!-5-methyl-2-thioxo-2,3-dihydro-1H-imi
dazole-4-carboxylate
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is hydro, R.sup.4 is methyl and R.sup.5 is
ethoxycarbonyl.
A solution of diisopropylamine (1.54 mL, 11 mmol) in 30 mL of dry THF under
argon was cooled to 0.degree. C. and n-butyllithium (6.25) mL, 10 mmol)
was added. The mixture was cooled to -78.degree. C. and
ethyl›(1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetate (1.33 g,
5.0 mmol), prepared as in Example 23, in 20 mL of THF was added over 15
minutes. The mixture was stirred at -78.degree. C. for 1 hour and acetyl
chloride (0.427 mL, 6.0 mmol) was added over 5 minutes. The mixture was
stirred for 3 hours at -78.degree. C. and then warmed to room temperature
over 1 hour. The solvent was removed by evaporation and the residue was
dissolved in 25 mL of 1N hydrochloric acid and 25 mL of ethanol. Potassium
thiocyanate (1.94 g, 20 mmol) was added and the mixture was stirred at
75.degree.-80.degree. C. for 18 hours. The mixture was cooled, diluted
with water and extracted twice with ethyl acetate. The ethyl acetate was
concentrated to a dark oil. Purification of the residue by, column
chromatography on silica gel (elution: 2% methanol/methylene chloride) and
trituration with ethyl acetate/isopropyl ether gave ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-1,3-dihydro-1H-imi
dazole-4-carboxylate, m.p. 225.degree.-227.degree. C., as a light yellow
solid.
Proceeding as in Example 25, but substituting a different material for
ethyl›(1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)amino!acetate and/or
acetyl chloride gave the following compounds of Formula I:
substituting isobutyryl chloride gave ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-prop-2-yl-2-thioxo-1,3-dihydro-1H-
imidazole-4-carboxylate, m.p. 195.degree.-197.degree. C.;
substituting trimethylacetyl chloride gave ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-(1,1-dimethylethyl)-2-thioxo-1,3-d
ihydro-1H-imidazole-4-carboxylate as a foam;
substituting
ethyl(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(formyl)-aminoacetate
gave ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-1,3-d
ihydro-1H-imidazole-4-carboxylate, m.p. 207.degree.-209.degree. C.; and
substituting ethyl oxalyl chloride gave ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-ethoxycarbonyl-2-thio
xo-1,3-dihydro-1H-imidazole-4-carboxylate, m.p. 160.degree.-161.degree. C.
EXAMPLE 26
5-Aminomethyl-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triaz
ole-3-thione
The following is the preparation of a compound of Formula I(b) in which n
is 1, t is 0 and R.sup.7 is aminoethyl.
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.19 g, 1.0
mmol), prepared as in Example 10, and
(tert-butyloxycarbonyl)aminoacetylhydrazide (0.19 g, 1.1 mmol) in 5 mL of
DMF under nitrogen was heated at 80.degree. C. for 2.5 hours. The solvent
was removed by rotary evaporation. The residue was stirred under nitrogen
at room temperature and a 4.5 mL of a mixture of sodium ethoxide (prepared
from 0.46 g of sodium and 45 mL of ethanol) was added. The reaction
mixture was refluxed under nitrogen for approximately 24 hours, allowed to
cool and then filtered. The solvent was removed by rotary evaporation and
the residue was dissolved in water. The solution was acidified to pH 3
with 10% hydrochloric acid and then filtered. Evaporation of the water
under reduced pressure gave
5-(tert-butyloxycarbonyl)aminomethyl-4-(1,2,3,4-tetrahydronaphthalen-2-yl)
-2,4-dihydro›1,2,4!triazole-3-thione (0.203 g, 0.56 mmol).
Anhydrous hydrogen chloride (4.22 g) was bubbled into 15 mL of ethyl
acetate in an ice-methanol bath.
5-(tert-Butyloxycarbonyl)aminomethyl-4-(1,2,3,4-tetrahydronaphthalen-2-yl)
-2,4-dihydro›1,2,4!triazole-3-thione (0.178 g, 0.49 mmol) was added and the
mixture was stirred at room temperature. Ether was added and the mixture
was filtered under nitrogen. Evaporation of the solvents under reduced
pressure gave
5-aminomethyl-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!!tri
azole-3-thione hydrochloride (0.125 g, 0.41 mmol) m.p.
279.degree.-281.degree. C.
Proceeding as in Example 26, but substituting a different starting material
for 2-isothiocyano-1,2,3,4-tetrahydronaphthalene and/or
(tert-butyloxycarbonyl)aminoacetylhydrazide gave the following compounds
of Formula I:
substituting 2-isothiocyano-1,2,3,4-tetrahydronaphthalene and
4-methylpiperazin-1-ylacetylhydrazide gave
5-(4-methylpiperazin-1-yl)-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihyd
ro›1,2,4!triazole-3-thione, m.p. 217.degree.-218.degree. C. and
substituting (S)-5,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene
and (tert-butyloxycarbonyl)aminoacetylhydrazide gave
(S)-5-aminomethyl-4-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-d
ihydro›1,2,4!triazole-3-thione and
(S)-5-aminomethyl-4-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-d
ihydro›1,2,4!triazole-3-thione hydrochloride, m.p. >280.degree. C.
EXAMPLE 27
2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triazole-3-thione
The following is the preparation of a compound of Formula I(c) in which n
is 1, t is 0 and R.sup.8 is hydro.
A mixture of 1,2,3,4-tetrahydronaphthalen-2-one (3.5 g, 24.0 mmol) and
formic hydrazide (1.56 g, 26.0 mmol) in 25 mL of ethanol and 1 drop of
concentrated hydrochloric acid was heated at 70.degree. C. for 1 hour. The
mixture was cooled to room temperature giving a crystalline material. The
material was isolated by filtration and washed with ethanol. Drying gave
2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.5 g, 8.7 mmol).
A mixture of 2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.0 g, 16.0
mmol) and sodium borohydride (1.2 g, 31.6 mmol) in 25 mL of ethanol was
stirred at room temperature for 20 hours. The mixture was quenched with
water and then extracted with ethyl acetate (2.times.50 mL). The combined
ethyl acetate extract was washed with brine, dried over sodium sulfate and
concentrated. Purification of the residue by flash chromatography
(elution: 2% methanol/methylene chloride) gave
2-formylhydrazo-1,2,3,4-tetrahydronaphthalene (2 g, 10.7 mmol).
A mixture of 2-formylhydrazo-1,2,3,4-tetrahydronaphthalene (2.0 g, 10.7
mmol) and trimethylsilyl isothiocyanate (2.8 g, 21.0 mmol) in 20 mL of
toluene was stirred at 60.degree. to 65.degree. C. for 20 hours giving a
crystalline material. Filtration and drying gave
N-›(1,2,3,4-tetrahydronaphthalen-2-yl)(aminothiocarbonyl)amino!formamide
(0.6 g, 2.4 mmol).
A solution of
N-›(1,2,3,4-tetrahydronaphthalen-2-yl)(aminothiocarbonyl)amino!formamide
(0.6 g, 2.4 mmol) in 10 mL of 10% sodium hydroxide was heated at
70.degree. C. for 30 minutes. The solution was cooled, acidified with
dilute hydrochloric acid and extracted with ethyl acetate. The ethyl
acetate extract was washed with brine, dried over sodium sulfate and
concentrated. The residue was recrystallized from ethyl acetate/hexane and
filtration gave
2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triazole-3-thione
(0.25 g. 1.06 mmol), m.p. 200.5.degree. C.
EXAMPLE 28
4-Amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4
!triazole-3-thione
The following is the preparation of a compound of Formula I(c) in which n
is 1, t is 0 and R.sup.8 is amino.
A mixture of 2-bromo-1,2,3,4-tetrahydronaphthalene (1.06 g, 5 mmol) and
4-amino›1,2,4!triazole (2.1 g, 25 mmol) in 8 mL of DMF was heated at
90.degree. C. and stirred for 2 hours. The solvents were removed by
evaporation and the residue was dissolved in 5 mL of pyridine. Lac sulfur
(0.16 g, 5 mmol) and 2.5 mL of triethylamine were added and the mixture
was heated at approximately 90.degree. C. and stirred under argon for 4
hours. The solvents were removed by evaporation and the residue was
co-evaporated with toluene (.times.2). Purification by flash
chromatography (elution: 3-5% methanol/methylene chloride) gave
4-amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triazole-3
-thione (0.35 g, 1.42 mmol), m.p. 147.degree.-150.degree. C.
EXAMPLE 29
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihy
dro-1H-imidazol-4-ylmethyl!formamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
formylaminomethyl.
Formamide (250 mL, 6.3 mol) was heated to 1750.degree. C. and
(S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione (25.0 g, 88.3 mmol), prepared as in Example 18,
was added in portions over 30 minutes and the reaction mixture was stirred
for 1 hour under a nitrogen sweep. The mixture was cooled to 500.degree.
C. and 2.5 g of activated carbon, Darco.RTM., was added. The mixture was
cooled to 30.degree. C., filtered through Celite and washed in with 25 mL
of formamide. The filtrate was heated to 95.degree. C. and then 1 L of
water was added dropwise. The mixture was allowed to cool and then stirred
at room temperature for 12 hours. The mixture was cooled to 0.degree. C.
giving a crystalline material. The material was isolated by filtration and
dried.
The material was stirred with approximately 5 times by weight of 70%
THF/30% hexanes for five minutes. The material was isolated by filtration
and the filter residue was washed with 50% THF/50% hexanes. Drying to
constant weight gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide (19.5 g, 62.7 mmol), m.p.
245.degree.-246.degree. C. ›.alpha.!.sub.D +48.9.degree. (c=0.613, DMSO).
Proceeding as in Example 29, but substituting different starting materials
for
(S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1,
3-dihydroimidazole-2-thione or formamide gave the following compounds of
Formula I(a):
substituting
(S)-5-hydroxymethyl-1-(6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione gave
(S)-N-›3-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide; and
substituting urea gave
(S)-5-ureidomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-
dihydroimidazole-2-thione, m.p. 258.degree.-260.degree. C., ›.alpha.!.sub.D
+34.3.degree. (C=0.574, DMSO).
EXAMPLE 30
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihy
dro-1H-imidazol-4-ylmethyl!formamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
formylaminomethyl.
A mixture of
(S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione (1.0 g, 3.5 mmol), prepared as in Example 18,
and ammonium formate (10 g, 158.6 mmol) was stirred at approximately
125.degree. C. for 1 hour. The mixture was then heated to approximately
138.degree. C. and stirred for an additional 35 minutes. The mixture was
diluted with 25 mL of water and allowed to cool to room temperature. The
mixture was aged for approximately 18 hours giving a crystalline material.
The material was isolated by filtration and the filter residue was washed
with water. Drying to constant weight gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide (0.92 g, 2.96 mmol).
Proceeding as in Example 30, but substituting ammonium acetate for ammonium
formate gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!acetamide, m.p. 275.5.degree.-276.degree. C.
dec. ›.alpha.!.sub.D +41.3.degree. (c=1.00, DMSO).
EXAMPLE 31
(S)-5-Aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-di
hydroimidazole-2-thione hydrochloride
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
aminomethyl.
A mixture of
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide (19.1 g, 59.0 mmol), prepared as in
Example 30, and 25 mL of concentrated hydrochloric acid (12.0M, 25 mL, 300
mmol) in 400 mL of isopropanol was heated to reflux over 12 minutes and
stirred for 1 hour 40 minutes. The mixture was distilled removing 150 mL
of isopropanol. The mixture was gradually cooled to room temperature and
stirred for 3 hours 45 minutes. The material was isolated by filtration
and the filter residue was washed with 75 mL of isopropanol. Drying in
vacuo at 110.degree. to 125.degree. C. with a nitrogen bleed gave
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride (15.6 g, 47.1 mmol), m.p.
251.9.degree. C. ›.alpha.!.sub.D +10.2.degree. C. (c=0.500, DMSO).
Proceeding as in Example 31, but substituting different starting materials
for
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!formamide gave the following compounds of
Formula I:
substituting
(S)-N-›3-(6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-yl-methyl!formamide gave
(S)-5-aminomethyl-1-(6,7-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione hydrochloride, m.p. 190.degree. C. dec;
substituting
(S)-4-{2-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen
-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!ethyl}benzoic acid gave
(S)-4-{2-›4-aminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)
-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!ethyl}benzoic acid hydrochloride,
m.p. 246.degree.-248.degree. C.; and
substituting
(S)-3-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!propionic acid gave
(S)-3-›4-aminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-
thioxo-2,3-dihydro-1H-imidazol-1-yl!propionic acid, m.p. 191.degree. C.
(eff.).
EXAMPLE 32
(S)-1-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-pyrrolidin-1-ylmet
hyl-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position, R.sup.3 and
R.sup.4 are hydro and R.sup.5 is pyrrolidin-1-ylmethyl.
A solution of
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3
-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18,
in 20 mL of THP and 1 drop of DMF was cooled to between 0.degree. and
5.degree. C. and thionyl chloride (13.7M, 109 .mu.L, 1.49 mmol) was added
drop-wise under a nitrogen atmosphere. The mixture was stirred at room
temperature for 0.5 hours, under reflux for 0.5 hours and again at room
temperature for 0.5 hours. The mixture then was cooled to between
0.degree. and 5.degree. C. and pyrrolidine (12.0M, 818 .mu.L, 9.8 mmol)
was added drop-wise. The mixture was stirred under reflux for 1.5 hours.
The solvents were removed by evaporation and the residue was diluted with
water. Ethyl acetate was added to the dilution and the mixture was
adjusted to pH 7. The ethyl acetate layer was dried and concentrated by
evaporation. Purification of the residue by column chromatography gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrr
olidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol).
›.alpha.!.sub.D.sup.25 =-10.96.degree. (c=1.3, DMSO).
Treatment with 2 molar equivalents of 1M anhydrous hydrogen chloride in
diethyl ether gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrr
olidin-1-ylmethyl)imidazole-2-thione hydrochloride (100 mg, 0.26 mmol),
m.p. 187.degree.-189.degree. C.
Proceeding as in Example 32, but substituting a different starting material
for
(S)-5-hydroxymethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione gave the following compounds of Formula I:
substituting methylamine gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(methylaminomethy
l)-1,3-dihydroimidazole-2-thione, m.p. 250.degree.-260.degree. C., and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(methylaminomethy
l)-1,3-dihydroimidazole-2-thione hydrochloride, m.p. 250.degree. C.,
›.alpha.!.sub.D.sup.25 =+7.7.degree. (c=2.4, DMSO);
substituting dimethylamine gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(dimethylaminomet
hyl)-1,3-dihydroimidazole-2-thione and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(dimethyl-aminome
thyl)-1,3-dihydroimidazole-2-thione hydrochloride, m.p.
207.degree.-208.degree. C.;
substituting piperidine gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(piperidin-1-ylme
thyl)-1,3-dihydroimidazole-2-thione and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(piperidin-1-ylme
thyl)-1,3-dihydroimidazole-2-thione hydrochloride, m.p.
169.degree.-170.degree. C.;
substituting morpholine gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(morpholin-4-ylme
thyl)-1,3-dihydroimidazole-2-thione, m.p. 198-201, ›.alpha.!.sub.D.sup.25
=-7.56.degree. (c=2.38, DMSO) and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(morpholin-4-ylme
thyl)-1,3-dihydroimidazole-2-thione hydrochloride, m.p.
182.degree.-184.degree. C.; and
substituting 1-methylpiperazine gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(4-methylpiperazi
n-1-ylmethyl)-1,3-dihydroimidazole-2-thione and
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(4-methylpiperazi
n-1-ylmethyl)-1,3-dihydroimidazole-2-thione hydrochloride, m.p.
237.degree.-245.degree. C.
EXAMPLE 33
1-(1,2,3,4-
Tetrahydronaphthalen-2yl)-4,5-dihydromethyl)-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is hydro and R.sup.4 and R.sup.5 are each
hydroxymethyl.
A mixture of sodium borohydride (0.22 g, 5.8 mmol) and anhydrous calcium
chloride 0.34 g, 3.1 mmol) in 10 mL of dry THF was stirred at
approximately 25.degree. C. for 1 hour and then ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-ethoxycarbonyl-2-thioxo-1,3-dihydr
o-1H-imidazole-4-carboxylate (0.37 g, 1 mmol), prepared as in Example 25,
in 10 mL of dry THF was added. The mixture was stirred at 50.degree. C.
for approximately 72 hours and then concentrated. The residue was treated
with 20 mL of 10% sodium hydroxide and 50 mL of ethyl acetate and filtered
and the aqueous phase was extracted again with ethyl acetate (3.times.50
mL). The combined extracts were dried (MgSO.sub.4) and concentrated. The
residue was stirred with methylene chloride/methanol (93:7) and the
mixture was filtered. The above aqueous phase was evaporated to dryness
and the residue was stirred with methanol. The methanol mixture was
filtered and then combined with the methylene chloride/methanol filtrate.
The combined mixture was concentrated and the residue was purified by
flash chromatography on silica gel eluting with methylene
chloride/methanol (93:7 to 96:4) to give
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(hydroxymethyl)-1,3-dihydroimi
dazole-2-thione (35 mg, 0.12 mmol), m.p. 199.degree.-200.degree. C.
EXAMPLE 34
Ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionate
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is 2-ethoxycarbonylethyl and R.sup.4 and R.sup.5 are
each hydro.
A mixture of
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.3
g, 5.6 mmol), prepared as in Example 9, and ethyl acrylate (3.1 mL, 28.2
mmol) in 14 mL of ethanol and 1.28 mL of N-benzyltrimethylammonium
hydroxide (2.8 mmol) in methanol was heated at 80.degree. C. under
nitrogen for 2 hours. The mixture was allowed to cool and concentrated by
rotoevaporation. The residue was purified by chromatography on silica gel
eluting with hexanes/ethyl acetate (3:1) to give ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionate (1.2 g, 3.7 mmol), m.p. 71.degree.-73.degree. C.
Proceeding as in Example 34, but substituting different starting materials
for 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione
gave the following compounds of Formula I:
substituting tert-butyl
4-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-thioxo-1,5-dihydro›1,2,4!triazol-3
-ylmethylaminoformate gave ethyl
3-›4-(1,2,3,4-tetrahydronaphthalen-2-yl)-3-(tert-butoxycarbonylaminomethyl
)-5-thioxo-1,5-dihydro›1,2,4!triazol-1-yl!propionate; and
substituting
(S)-(1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazo
le-2-thione gave
ethyl(S)-3-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,
3-dihydro-1H-imidazol-1-yl!propionate, m.p. 105.degree.-1070.degree. C.
EXAMPLE 35
Ethyl 3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl
2-thioxo-2,3-dihydro-1H-imidazol-1-yl!propionate
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is 2-(ethoxycarbonyl)ethyl, R.sup.4 is hydro and
R.sup.5 is dimethylaminomethyl.
A mixture of ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionate (0.5 g, 1.5 mmol), prepared as in Example 34, and
N,N-dimethylmethyleneammonium chloride (0.17 g, 1.8 mmol) in 7 mL of DMF
was heated at 80.degree. C. under nitrogen for 16 hours. The mixture then
was partitioned between saturated sodium bicarbonate solution and ethyl
acetate. The organic layer was separated, washed with brine, dried
(NaSO.sub.4), filtered and concentrated. The residue was purified by
column chromatography on silica gel eluting with ethyl acetate/hexane to
give ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl-2-thioxo-2,
3-dihydro-1H-imidazol-1-yl!propionate (277 mg, 0.7 mmol), m.p.
128.degree.-130.degree. C.
Proceeding as in Example 35 but substituting methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-ylmethyl!benzoate for ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionate gave methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylamino-5-methyl-2-thioxo
-2,3-dihydro-1H-imidazol-1-ylmethyl!benzoate, as a foam.
EXAMPLE 36
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylamino)-1,3-dihydroimid
azole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is hydro and R.sup.4 and R.sup.5 are each
dimethylaminomethyl.
A mixture of
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-imidazole-2-thione (1 g,
4.3 mmol), prepared as in Example 9, ethyl acrylate (4.7 mL, 43 mmol) and
hydrochloric acid (1N in ether, 8.7 mL, 8.7 mmol) in 20 mL of ethanol was
heated at 80.degree. C. under nitrogen for approximately 5 hours. The
mixture was allowed to cool, concentrated and partitioned between
saturated sodium bicarbonate solution and methylene chloride. The organic
layer was separated and dried (K.sub.2 CO.sub.3), filtered and
concentrated. The residue was purified by column chromatography on silica
gel eluting with methylene chloride/methanol (99:1) to give ethyl
3-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazol-2-yl-thio!propionate
(1.36 g, 4.1 mmol).
A mixture of ethyl
3-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)-imidazol-2-ylthio!propionate
(1.36 g, 4.1 mmol) and N,N-dimethylmethylene ammonium chloride (1.66 g,
17.7 mmol) in 25 mL of DMF was heated at 100.degree. C. under nitrogen for
approximately 22 hours. The reaction mixture was allowed to cool to
approximately 90.degree. C. and then additional
N,N-dimethylmethyleneammonium chloride (0.83 g, 8.8 mmol) was added. The
mixture was heated for 31.5 hours and then partitioned between sodium
bicarbonate and ethyl acetate. The organic layer was separated, washed
with brine, dried (K.sub.2 CO.sub.3), filtered and concentrated. The
residue was purified by column chromatography on silica gel eluting with
5-10% methanol in methylene chloride to give ethyl
3-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylaminomethyl)imidaz
ol-2-ylthio!propionate (0.55 g, 1.2 mmol).
A mixture of ethyl
3-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylaminomethyl)imidaz
ol-2-ylthio!propionate (0.55 g, 1.2 mmol) and sodium ethoxide (3.5 mL of a
solution prepared free 450 mg sodium in 45 mL of ethanol, 1.4 mmol) in 5
mL of ethanol was stirred at approximately 25.degree. C. for 1.75 hours.
The mixture was concentrated and partitioned between water and ethyl
acetate. The organic layer was separated, washed with brine, dried
(K.sub.2 CO.sub.3), filtered and concentrated. The residue was purified by
column chromatography on silica gel eluting with methylene
chloride/methanol (97:3) to give
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylamino)-1,3-dihydroimi
dazole-2-thione (0.24 g, 0.7 mmol), m.p. 182.degree.-184.degree. C.
EXAMPLE 37
3-(5-7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-
imidazole-4-carboxylic acid
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position, R.sup.3 and
R.sup.4 are hydro and R.sup.5 is carboxy.
A mixture of ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate (4.6 g, 13.6 mmol), prepared as in Example 24, and
potassium hydroxide (3.14 g, 47.6 mmol) in 130 mL of ethanol/water (10:3)
was stirred at 85.degree.-90.degree. C. for 5 hours. The solvent was
removed by evaporation and the residue was dissolved in water. The
solution was acidified with 1N hydrochloric acid to a pH of 1 giving a
crystalline material. Isolation of the material by filtration gave
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylic acid (3.86 g, 12.5 mmol), m.p.
250.degree.-252.degree. C.
Proceeding as in Example 37, but substituting a different starting material
for ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate gave the following compounds of Formula I(a):
substituting ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-
carboxylate gave ethyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-
carboxylic acid, m.p. 231.degree.-332.degree. C. (dec);
substituting ethyl
3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imi
dazole-4-carboxylate gave ethyl
3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imi
dazole-4-carboxylic acid, m.p. 207.degree.-209.degree. C.;
substituting ethyl
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate gave
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylic acid, m.p. 207.degree.-208.degree. C., and treating
with potassium hydroxide in methanol, evaporating to dryness and
recrystallizing from methanol/isopropanol gave potassium
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate, m.p. 160.degree.-163.degree. C.;
substituting ethyl
3-(4,6-difluoroindan-1-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
gave
3-(4,6-difluoroindan-1-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic
acid and treating with potassium hydroxide in methanol, evaporating to
dryness and recrystallizing from methanol/isopropanol gave potassium gave
potassium
3-(4,6-difluoroindan-1-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
, m.p. 163.degree.-173.degree. C.;
substituting ethyl
3-(5,7-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
gave
3-(5,7-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic
acid, m.p. 230.degree.-232.degree. C., and treating with potassium
hydroxide in methanol, evaporating to dryness and recrystallizing from
methanol/isopropanol gave potassium
3-(5,7-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
, m.p. 170.degree.-174.degree. C.;
substituting ethyl
3-(5,6-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylate
gave
3-(5,6-difluoroindan-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic
acid, m.p. 233.degree.-234.degree. C.;
substituting methyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoate and sodium hydroxide gave
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoic acid, m.p. 252.degree.-254.degree. C.;
substituting methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoate and sodium hydroxide gave
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!benzoic acid, m.p. 211.degree.-212.degree. C.;
substituting methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!butyrate gave
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!butyric acid, m.p. 156.degree.-158.degree. C.;
substituting methyl
5-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!picolinate and recrystallizing from a solution of hydrochloric
acid in ethanol gave
5-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylmethyl!picolinic acid hydrochloride, m.p. 204.degree.-205.degree. C.;
substituting methyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionate gave
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionic acid, m.p. 167.degree.-168.degree. C.;
substituting methyl
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-ylmethyl!benzoate gave
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-methyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-ylmethyl!benzoic acid, m.p. 181.degree.-182.degree. C.;
substituting ethyl
3-›4-(1,2,3,4-tetrahydronaphthalen-2-yl)-3-(tert-butoxycarbonylaminomethyl
)-5-thioxo-1,5-dihydro›1,2,4!triazol-1-yl!propionate gave
3-›4-(1,2,3,4-tetrahydronaphthalen-2-yl)-3-(tert-butoxycarbonylaminomethyl
)-5-thioxo-1,5-dihydro›1,2,4!triazol-1-yl!propionic acid, m.p. 76-78;
substituting
ethyl(S)-3-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,
3-dihydro-1H-imidazol-1-yl!propionate gave
(S)-3-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-1-yl!propionic acid, m.p. 182.degree.-184.degree. C.;
substituting ethyl
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl-2-thioxo-2,
3-dihydro-1H-imidazol-1-yl!propionate gave
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl-2-thioxo-2,
3-dihydro-1H-imidazol-1-yl!propionic acid, m.p. 171.degree.-174.degree. C.;
substituting
methyl(S)-4-{2-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro
-1H-imidazol-4-yl-methylamino!ethyl}benzoate gave
(S)-4-{2-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-im
idazol-4-ylmethylamino!ethyl}benzoic acid hydrochloride, m.p.
240.degree.-241.degree. C.; and
substituting
ethyl(S)-3-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthal
en-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!propionate gave
(S)-3-›4-formylaminomethyl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl!propionic acid.
Proceeding as in Example 37, but substituting a different starting material
for ethyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carboxylate and performing an acid catalyzed hydrolysis gave
the following compounds of Formula I(a):
substituting tert-butyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-y
lacetate and trifluoroacetic acid gave
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-y
l-acetic acid, m.p. 228.degree.-230.degree. C.;
substituting tert-butyl
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazol-4-ylmethylaminoacetate and hydrochloric acid gave
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazol-4-ylmethylaminoacetic acid hydrochloride, m.p.
214.degree.-216.degree. C.;
substituting
tert-butyl(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-ylmethylaminoacetate and hydrochloric acid gave
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazol-4-ylmethylaminoacetic acid hydrochloride, m.p. 214.degree. C.
(eff.); and
substituting tert-butyl
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-y
lmethylaminoacetate and hydrochloric acid gave
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-y
lmethylaminoacetic acid hydrochloride, m.p. 208.degree.-211.
EXAMPLE 38
4-›3-(1,2,3,4-Tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1
-yl!butyramide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is 4-(carbamoyl)propyl and R.sup.4 and R.sup.5 are
each hydro.
A mixture
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!butyric acid (100 mg, 0.32 mol), prepared as in Example 37, oxalyl
chloride (2M, 0.32 mL, 0.64 mol) and 5 drops of DMF in 10 mL of methylene
chloride was stirred for 2 hours. Solvents and excess oxalyl chloride were
removed by evaporation and the residue was treated with 5 mL of 30%
aqueous ammonium hydroxide and stirred for 16 hours. The mixture was
poured into aqueous sodium bicarbonate and extracted with methylene
chloride. The extract was dried (Na.sub.2 SO.sub.4) and concentrated. The
residue was purified by flash chromatography on silica gel eluting with
methylene chloride/methanol (99:1 to 96:4) to give
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!butyramide (70 mg, 0.22 nmol), as a foam.
Proceeding as in Example 38, but substituting different starting materials
for
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!butyric acid gave the following compounds of Formula I:
substituting
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylethyl!benzoic acid gave
4-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-ylethyl!benzamide, m.p. 158.degree.-160.degree. C.; and
substituting
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionic acid gave
3-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
1-yl!propionamide, m.p. 180.degree.-181.degree. C.
EXAMPLE 39
3-›2-(4(1H-Tetrazol-5-ylphenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)
-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.1 is 2-(4(1H)-tetrazol-5-ylphenyl)ethyl and R.sup.4
and R.sup.5 are hydro.
A mixture
3-›2-(4-cyanophenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione (0.5 g, 1.4 mmol), prepared as in Example 15, and
tributyltin azide (1.39 g, 4.2 mmol) in 3 mL of xylene was heated at
120.degree. C. under nitrogen for approximately 16 hours. The mixture was
purified by chromatography on silica gel eluting with methylene
chloride/methanol and the purified product was recrystallized from ethyl
acetate/methanol to give
3-›2-(4(1H)-tetrazol-5-ylphenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-y
l)-1,3-dihydroimidazole-2-thione (0.5 g, 1.4 nmol), m.p.
218.degree.-220.degree. C.
EXAMPLE 40
(S)-4-(1-hydroxy)ethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1
,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 and R.sup.5 are each hydro and R.sup.4 is
1-hydroxyethyl.
A mixture of
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazole-5-carbaldehyde (178 mg, 0.6 mmol), prepared as in Example
22, and methylmagnesium chloride (3M, 0.4 mL, 1.2 mmol) was stirred at
approximately 0.degree. C. for 1 hour and at approximately 25.degree. for
an additional 1 hour. The mixture was treated with 5 mL of dilute sulfuric
acid and extracted with ethyl acetate (2.times.). The combined extracts
were dried (MgSO.sub.4) and concentrated and the residue was purified by
flash chromatography on silica gel eluting with methylene
chloride/methanol (98:2). The purified residue was further purified by
preparative thin layer chromatography on silica gel eluting with methylene
chloride/methanol (95:5) to give
(S)-4-(1-hydroxy)ethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-
1,3-dihydroimidazole-2-thione (22 mg, 0.1 mmol), m.p.
210.degree.-211.degree. C.
Proceeding as in Example 40, but substituting n-propylmagnesium chloride
for methylmagnesium chloride gave
(S)-4-(1-hydroxy)but-1-yl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-y
l)-1,3-dihydroimidazole-2-thione, m.p. 154.degree.-156.degree. C.
EXAMPLE 41
N-1H-Tetrazol-5-yl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thi
oxo-2,3-dihydro-1H-imidazole-4-carboxamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
1H-tetrazol-5-yl-carbamoyl.
3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-Z,3-dihydro-1H-
imidazole-4-carboxylic acid (1 g, 3.33 mmol), prepared as in Example 37,
was dissolved in 15 mL of oxalyl chloride and 1 drop of DMF and the
solution was stirred under nitrogen for 3 hours. The excess oxalyl
chloride was removed by rotary evaporation and the residue was
co-evaporated with carbon tetrachloride (2.times.25 mL). The residue was
cooled at 0.degree. C. and dry 5-amino-1H-tetrazole (0.85 g, 10 mmol) and
25 mL of pyridine were added. The mixture was allowed to warm to room
temperature and then stirred for 16 hours. The solvent was removed by
evaporation and the residue was co-evaporated with toluene. Purification
of the residue by column chromatography on silica gel packed in 5%
methanol/methylene chloride containing 1% acetic acid gave 0.9 g of impure
product. The impure product was dissolved in aqueous potassium carbonate
and the solution was extracted with ethyl acetate. The aqueous layer was
acidified giving a solid material. Isolation of the material by filtration
gave
N-1H-tetrazol-5-yl-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-th
ioxo-2,3-dihydro-1H-imidazole-4-carboxamide (0.54 g, 1.56 mmol) as a light
orange solid, m.p. 228.degree.-230.degree. C.
EXAMPLE 42
(4-
Methylpiperazin-1-yl)›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2
-thioxo-2,3-dihydro-1H-imidazol-4-yl!methanone
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
4-methylpiperazin-1-ylcarbonyl.
A mixture of
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid, prepared as in Example 37, (0.75 g, 2.42
mmol) and 1,1'-carbonyldiimidazole (0.43 g, 2.65 mmol) in 6 mL of THF was
stirred under argon at room temperature for approximately 18 hours.
N-Methylpiperazine (0.29 mL, 2.65 mmol) was added and the mixture was
stirred under argon at rote temperature for approximately 18 hours. The
mixture was partitioned between methylene chloride and water. The
methylene chloride layer was washed 4 times with water, dried over
magnesium sulfate and concentrated by evaporation. Recrystallization of
the residue from ethyl acetate/methanol gave
(4-methylpiperazin-1-yl)›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl!methanone (0.69 g, 1.76 mmol),
248.degree.-250.degree. C.
Proceeding as in Example 42, but substituting a different starting material
for
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid and/or N-methylpiperazine gave the following
compounds of Formula I:
substituting
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid gave
(4-methylpiperazin-1-yl)›3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl!methanone as an oil;
substituting
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid and N,N-dimethylethylenediamine gave
N-(2-dimethylaminoethyl)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl
)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxamide, m.p. 125.degree. C.;
substituting
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid and p-methylsulfonylaminoaniline gave
N-›4-(methylsulfonylamino)phenyl!-3-(5,7-difluoro-1,2,3,4-tetrahydronaphth
alen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxamide, m.p.
225.degree.-230.degree. C.;
substituting
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid and dimethylaminoethanethiol hydrochloride in
the presence of dichlorohexylcarbodiimide gave
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carbothioic acid S-(2-dimethylaminoethyl) ester, m.p.
204.degree.-206.degree. C.; and
substituting
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-1H
-imidazole-4-carboxylic acid and dimethylaminoethanethiol hydrochloride in
the presence of dichlorohexylcarbodiimide gave
3-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-4-carbothioic acid S-(2-dimethylaminoethyl)ester, m.p.
275.degree.-277.degree. C.
EXAMPLE 43
3-(3,4-Dihydroxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroim
idazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 is 3,4-dihydroxybenzyl and R.sup.4 and R.sup.5 are
each hydro.
A solution of
3-(3,4-dimethoxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroi
midazole-2-thione (900 mg, 2.37 mol), prepared as in Example 15, in
methylene chloride was cooled to 0.degree. C. under nitrogen and then
boron tribromide (1M, 7.1 mL, 7.1 mmol) in an additional 10 mL of
methylene chloride was added dropwise. The mixture was allowed to cool to
room temperature, stirred for 16 hours and then slowly added to water. The
organic layer was separated, washed with brine, dried (Na.sub.2 SO.sub.4)
and concentrated. The residue was purified by flash chromatography on
silica gel eluting with methylene chloride/methanol (96:4) and then
crystallized from methanol/ethanol/hexane to give
3-(3,4-dihydroxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroi
midazole-2-thione (520 mg), m.p. 173.degree.-174.degree. C.
Proceeding as in Example 43, but substituting different starting materials
for
3-(3,4-dimethoxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroi
midazole-2-thione gave the following compounds of Formula I:
substituting
3-›2-(3,4-dimethoxyphenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione gave
3-›2-(3,4-dihydroxyphenyl)ethyl!-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3
-dihydroimidazole-2-thione, m.p. 165.degree.-167.degree. C.;
substituting 1-(5-methoxyindan-1-yl)-1,3-dihydroimidazole-2-thione gave
1-(5-hydroxyindan-1-yl)-1,3-dihydroimidazole-2-thione, m.p.
208.degree.-209.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-6-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-6-hydroxynaphthalen-1-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 213.degree.-215.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-5-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-5-hydroxynaphthalen-1-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 188.degree.-190.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-7-hydroxynaphthalen-1-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 195.degree.-196.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-5-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-5-hydroxynaphthalen-2-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 263.degree.-265.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-6-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-6-hydroxynaphthalen-2-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 240.degree.-241.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-7-hydroxynaphthalen-2-yl)-1,3-dihydro-imidazole-2-th
ione, m.p. 248.degree.-250.degree. C.;
substituting
1-(1,2,3,4-tetrahydro-8-methoxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one gave
1-(1,2,3,4-tetrahydro-8-hydroxynaphthalen-2-yl)-1,3-dihydroimidazole-2-thi
one, m.p. 274.degree.-276.degree. C.; and
substituting
1-(6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalen-2-yl)-1,3-dihydroim
idazole-2-thione gave
1-(6,8-difluoro-1,2,3,4-tetrahydro-7-hydroxynaphthalen-2-yl)-1,3-dihydroim
idazole-2-thione, m.p. 258.degree.-260.degree. C.
EXAMPLE 44
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihy
dro-1H-imidazol-4-ylmethyl!-4-butylbenzamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
4-butylbenzoylaminomethyl.
A mixture of
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione (0.30 g, 1 mmol), prepared as in Example 31, and
4-butylbenzoyl chloride (0.21 mL, 1.1 mmol) in 10 mL of dry pyridine was
stirred under argon at approximately 0.degree. C. for 1 hour and then at
approximately 25.degree. C. for an additional 2 hours. The mixture was
concentrated and the residue was treated with water. The mixture was
extracted with ethyl acetate (3.times.) and the combined extracts were
dried (MgSO.sub.4) and concentrated. The residue was recrystallized from
ethyl acetate to give
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!-4-butylbenzamide (0.25 g, 0.55 mmol), m.p.
242.degree.-243.degree. C.
Proceeding as in Example 44, but substituting different starting materials
for
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and/or 4-butylbenzoyl chloride gave the following
compounds of Formula I:
substituting nicotinoyl chloride hydrochloride gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!-nicotinamide, m.p. 218.degree.-221.degree. C.;
substituting benzoyl chloride gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!benzamide, m.p. 260.degree.-261.degree. C.;
substituting dimethylcarbamyl chloride gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!dimethylcarbamide, m.p. 218.degree.-220.degree.
C.;
substituting methyl chloroformate gave
methyl(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-
dihydro-1H-imidazol-4-ylmethylcarbamate, m.p. 220.degree.-222.degree. C.;
substituting
(S)-3-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-t
hione and acetic anhydride gave
N-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-
4-yl!acetamide, m.p. 196.degree.-200.degree. C.;
substituting 2-furancarboxylic acid chloride gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!-2-furancarboxamide, m.p.
227.degree.-231.degree. C.; and
substituting
4-amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2,4!triazole-3
-thione and acetic anhydride gave
N-›1-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-thioxo-4,5-dihydro-1H-›1,2,4!tr
iazol-4-yl!acetamide, m.p. 199.degree.-201.degree. C.
EXAMPLE 45
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihy
dro-1H-imidazol-4-ylmethyl!picolinamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
picolinoylaminomethyl.
A mixture of
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione (295 mg, 1 mmol), prepared as in Example 31,
picolinic acid (123 mg, 1 mmol) and PyBOP (620 mg, 1.2 mmol) in 10 mL of
dry DMF was stirred under argon at approximately 25.degree. C. for 5
minutes and then N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) was added.
The mixture was stirred for approximately 12 hours and then 10 mL of water
was added. The aqueous layer was extracted with ethyl acetate (3.times.10
mL) and the combined extracts were washed with water, dried (MgSO.sub.4)
and concentrated. The residue was purified by flash chromatography on
silica gel eluting with hexane/THF (1:1 to 8:2) to give
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!picolinamide (80 mg, 0.2 mmol), m.p.
216.degree.-217.degree. C.
Proceeding as in Example 45, but substituting a different starting material
for picolinic acid gave the following compounds of Formula I:
substituting N-(tert-butoxycarbonyl)glycine and deprotecting gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!aminoacetamide, m.p. 144.degree.-153.degree.
C.;
substituting N-(tert-butoxycarbonyl)-2-methylalanine and deprotecting gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!-2-amino-2-methylpropionamide trifluoroacetate,
m.p. 158.degree. C.; and substituting 5-butylpicolinic acid gave
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!-5-butylpicolinamide, m.p.
99.degree.-104.degree. C.
EXAMPLE 46
(S)-N-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihy
dro-1H-imidazol-1-4-ylmethyl!ethylcarbamide
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
ethyluriedomethyl.
A mixture of
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione (294 mg, 1 mmol), prepared as in Example 31, and
ethyl isocyanate (0.16 mL, 2 mmol) in 10 mL of THF was stirred at
approximately 50.degree. C. under argon for approximately 60 hours. The
mixture was filtered and the filtered solid was recrystallized from ethyl
acetate/methanol to give
(S)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dih
ydro-1H-imidazol-4-ylmethyl!ethylcarbamide (110 mg, 0.3 mmol), m.p.
219.degree.-220.degree. C.
EXAMPLE 47
4-Aminoethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-t
hione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 0, R.sup.3 and R.sup.5 are each hydro and R.sup.4 is
aminomethyl.
A mixture of
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-4-
carbaldehyde (0.25 g, 1.0 mmol), hydroxylamine hydrochloride (0.09 g, 1.3
mmol) and sodium hydroxide (0.064 g, 1.6 mmol) in 2 mL of ethanol and 2 mL
of water was stirred at 60.degree. C. for 1 hour. The mixture was cooled
giving a crystalline material. The material was isolated by filtration and
dried. The filtrate was stirred with ethyl acetate giving more crystalline
material. The material was isolated by filtration and dried. Combining the
crystalline material gave
1-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-
carbaldehyde oxime (0.186 g, 0.68 mmol).
A suspension of
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-
carbaldehyde oxime (0.158 g, 0.58 mmol), prepared as in Example 22, in 20
mL of THF was cooled to 0.degree. C. and LAH (1.0M, 1.16 mL, 1.16 mmol) in
THF was added slowly. The mixture was stirred at 0.degree. C. for 1 hour
and then saturated ammonium chloride, water and ethyl acetate were added.
The aqueous layer was separated and extracted with ethyl acetate. The
combined ethyl acetate was dried over magnesium sulfate and concentrated
by evaporation. Purification of the residue by flash chromatography
(elution: 3-10% methanol/methylene chloride) gave
4-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2
-thione, m.p. 197.degree.-200.degree. C.
EXAMPLE 48
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(2-phenylethyl)ami
nomethyl-1,3-dihydroimidazole-2-thione
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.4 is
2-(phenyl)ethylaminomethyl.
A mixture of
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazole-5-carbaldehyde (147 mg, 0.5 mmol), prepared as in Example
22, phenethylamine (75 .mu.L, 0.6 mmol) and sodium cyanoborohydride (47
mg, 0.75 mmol) in 10 mL of methanol was stirred at approximately
60.degree. C. for 2 hours. The mixture was concentrated and the residue
was purified by flash chromatography on silica gel eluting with methylene
chloride/methanol (97:3). The purified product was concentrated, converted
to the hydrochloride salt and recrystallized from ethyl acetate/methanol
to give
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-4-(2-phenylethyl)am
inomethyl-1,3-dihydroimidazole-2-thione hydrochloride (68 mg, 0.2 mmol),
m.p. 227.degree.-229.degree. C.
Proceeding as in Example 48, but substituting a different starting material
for
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazole-5-carbaldehyde and/or phenethylamine gave the following
compounds of Formula I:
substituting
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazole-5-carbaldehyde and glycine tert-butyl ester hydrochloride gave
tert-butyl
3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H
-imidazol-5-ylmethylaminoacetate;
substituting
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazole-5-carbaldehyde and glycine tert-butyl ester hydrochloride
gave
tert-butyl(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-
2,3-dihydro-1H-imidazol-5-ylmethylaminoacetate;
substituting
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-
carbaldehyde and glycine tert-butyl ester hydrochloride gave tert-butyl
3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-5-y
lmethylaminoacetate;
substituting glycinamide hydrochloride gave
(S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydr
o-1H-imidazol-5-yl-methylaminoacetamide, m.p. 212.degree.-213.degree. C.;
and
substituting methyl 4-(2-aminoethyl)benzoate hydrochloride gave
methyl(S)-4-{2-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thiox
o-2,3-dihydro-1H-imidazol-5-yl-methylamino!ethyl}benzoate, m.p.
159.degree.-160.degree. C.
EXAMPLE 49
(S)-N.sup.3
-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!-N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)formamidine
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)amidinoaminomethyl.
A mixture of
(S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-aminomethyl-1,3-d
ihydroimidazole-2-thione (0.6 g, 2 mmol), prepared as in Example 31, and
N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)methylthioamidine (0.65 g, 2.2
mmol) in 15 mL of THF and 0.3 mL of water was stirred at approximately
50.degree. C. under argon for 4 hours. The mixture was concentrated and
the residue was combined with 5% aqueous sodium bicarbonate. The mixture
was extracted with ethyl acetate and the extract was dried (MgSO.sub.4)
and concentrated. The residue was purified by flash chromatography on
silica gel eluting with methylene chloride/methanol (99:1) to give
(S)-N.sup.3
-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!-N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)formamidine
(0.54 g, 1 mmol), m.p. 155.degree. C. (eff.).
Proceeding as in Example 49, but subsituting a different starting material
for N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)methylthioamidine gave the
following compounds of Formula I:
substituting N.sup.1,N.sup.2 -di(acetyl)methylthioamidine gave (S)-N.sup.3
-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!N.sup.1,N.sup.2 -di(acetyl)formamidine, m.p.
213.degree.-214.degree. C.; and substituting N.sup.1
-(tert-butoxycarbonyl)methylthioamidine gave
(S)-N.sup.3
-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-yl-methyl!-N.sup.1 -(tert-butoxycarbonyl)formamidine,
m.p.>280.degree. C.
EXAMPLE 50
(S)-N.sup.3
-›3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!formamidine
The following is the preparation of a compound of Formula I(a) in which n
is 1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.5 is
amidinoaminomethyl.
A solution of (S)-N.sup.3
-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!-N.sup.1,N.sup.2 -di(tert-butoxycarbonyl)formamidine
(0.34 g, 0.6 mmol), prepared as in Example 50, in 20 mL of trifluoroacetic
acid was stirred at approximately 25.degree. C. for 1.5 hours. The
solution was concentrated and the residue was combined with 100 mL of
diethyl ether. The diethyl ether was decanted away and the residue was
combined with 100 mL of diethyl ether. The mixture was filtered and the
filtered residue was dissolved in ethyl acetate. The solution was
concentrated, evacuated and the resulting foam was treated with diethyl
ether. The mixture was filtered to give (S)-N.sup.3
-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-
1H-imidazol-4-ylmethyl!formamidine trifluoroacetate (0.28 g, 0.6 mmol),
m.p. 103.degree. (eff).
EXAMPLE 51
2S-Amino-3-(3H-imidazol-4-yl)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthal
en-2R-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl!propionamide
hydrochloride
The following is the preparation of a compound of Formula II in which n is
1, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.18 is a
group of Formula (d) wherein R.sup.21 is L-histidylaminomethyl.
A mixture of
(R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,d-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione (0.55 g, 1.86 mmol), prepared as in Example 31,
(S)-2-(tert-butoxycarbonyl)amino-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl
)propionic acid (0.76 g, 1.86 mol) and PyBOP (1.07 g, 2.05 mmol) in 6.2 mL
of DMF was stirred under argon until homogeneous.
Diethylisopropylethylamine (1.07 mL, 6.15 mmol) was added and the mixture
was stirred for approximately 18 hours. The mixture partitioned between
water and ethyl acetate and the organic layer was washed twice with water,
dried over magnesium. sulfate and concentrated by evaporation.
Purification of the residue by column chromatography (elution: 5%
methanol/methylene chloride) gave
2S-(tert-butoxy-carbonyl)amino-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl)-
N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2R-yl)-2-thioxo-2,3-dihydro
-1H-imidazol-4-yl-methyl!propionamide (1.003 g) as a foam.
2S-(tert-Butoxycarbonyl)amino-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl)-N-
›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2R-yl)-2-thioxo-2,3-dihydro-1
H-imidazol-4-ylmethyl!propionamide (0.935 g) was dissolved in 45 mL of 30%
anhydrous hydrogen chloride/ethyl acetate and the mixture was stirred for
18 hours giving a crystalline material. Isolation of the material by
filtration and drying at 60.degree. C. under vacuum gave
2S-amino-3-(3H-imidazol-4-yl)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphtha
len-2R-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl!propionamide
hydrochloride (0.655 g, 1.24 mmol), m.p. 228.degree. C.
Proceeding as in Example 51, but substituting a starting material for
(R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and/or
(S)-2-(tert-butoxycarbonyl)amino-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl
)propionic acid gave the following compounds of Formula II:
substituting
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione and
(S)-3-tert-butoxycarbonyl-2-tert-butoxycarbonylaminopropionic acid gave
3S-amino-N-›3-(5,7-difluoro-1,2,3,
4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl!s
uccinamic acid hydrochloride, m.p. 220.degree. C.;
substituting
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione and
(S)-3-(tert-butoxycarbonyl)-3-(tert-butoxycarbonylamino)propionic acid
gave 2S-amino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thio
xo-2,3-dihydro-1H-imidazol-4-ylmethyl!succinamic acid hydrochloride, m.p.
220.degree. C.;
substituting
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)1,3-dihydr
oimidazole-2-thione and (S)-2,5-di(tert-butoxycarbonylamino)valeric acid
gave
2S,5-diamino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thiox
o-2,3-dihydro-1H-imidazol-4-ylmethyl!valeramide hydrochloride, m.p.
212.degree.-216.degree. C.;
substituting
5-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2
-thione and (S)-2,5-di(tert-butoxycarbonylamino)valeric acid gave
2S,5-diamino-N-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro
-1H-imidazol-4-ylmethyl!valeramide hydrochloride, m.p.
191.degree.-205.degree. C.;
substituting
5-aminomethyl-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2
-thione and
(S)-2-(tert-butoxycarbonylamino)-5-(tert-butoxycarbonyl)guanidinovaleric
acid gave
2S-amino-N-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-
imidazol-4-ylmethyl!-5-guanidinovaleramide hydrochloride, m.p. 160.degree.
C.;
substituting
3-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thion
e and (S)-2-(tert-butoxycarbonyl)amino
-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl)propionic acid gave
2S-amino-3-(3H-imidazol-4-yl)-N-›3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-t
hioxo-2,3-dihydro-1H-imidazol-1-yl!propionamide hydrochloride, m.p.
197.degree.-205.degree. C.;
substituting
5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihyd
roimidazole-2-thione and
(S)-2-(tert-butoxycarbonyl)amino-3-(3-tert-butoxycarbonyl-3H-imidozol-4-yl
) propionic acid gave
2S-amino-3-(3H-imidazol-4-yl)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphtha
len-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl!propionamide
hydrochloride, m.p. 195.degree.-238.degree. C.;
substituting
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and
(S)-2-tert-butoxycarbonylamino-3-(3-tert-butoxycarbonyl-3H-imidazol-4-yl)p
ropionic acid gave
2S-amino-3-(3H-imidazol-4-yl)-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphtha
len-2S-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl!propionamide
hydrochloride, m.p. 225.degree. C.;
substituting
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and (S)-4-acetylamino-4-tert-butoxycarbonylbutyric
acid gave
2S-acetylamino-4-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2S-yl)-2-th
ioxo-2,3-dihydro-1H-imidazol-4-ylmethylaminocarbonyl!butyric acid, m.p.
159.degree. C.;
substituting
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and (S)-2,5-di(tert-butoxycarbonylamino)pentanoic
acid gave
2S,5-diamino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2S-yl)-2-thio
xo-2,3-dihydro-1H-imidazol-4-ylmethyl!valeramide hydrochloride, m.p.
233.degree.-237.degree. C.;
substituting
(R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and (S)-2,5-di(tert-butoxycarbonylamino)pentanoic
acid gave
2S,5-diamino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2R-yl)-2-thio
xo-2,3-dihydro-1H-imidazol-4-ylmethyl!valeramide hydrochloride, m.p.
128.degree.-150.degree. C.;
substituting
(S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and
(S)-3-(tert-butoxycarbonyl)-2-(tert-butoxycarbonylamino)propionic acid
gave 3S-amino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2S-yl)-2-thi
oxo-2,3-dihydro-1H-imidazol-4-ylmethyl!succinamic acid hydrochloride, m.p.
194.degree. C.;
substituting
(R)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-d
ihydroimidazole-2-thione and
(S)-3-(tert-butoxycarbonyl)-2-(tert-butoxycarbonylamino)propionic acid
gave 3S-amino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2R-yl)-2-thi
oxo-2,3-dihydro-1H-imidazol-4-ylmethyl!succinamic acid hydrochloride, m.p.
193.degree. C.;
substituting
4-amino-2-(5,7-difluoro-1,2,3,4-tetrahydronaphth-2-yl)-2,4-dihydro›1,2,4!t
riazole-3-thione and (S)-2,5-di(tert-butoxycarbonylamino)valeric acid gave
2S,5-diamino-N-›1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-thiox
o-4,5-dihydro-1H-›1,2,4!triazol-4-yl!valeramide hydrochloride;
substituting
4-amino-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2
,4!triazole-3-thione and
(S)-2-(tert-butoxycarbonyl)amino-3-(3-tert-butoxycarbonyl-!H-imidazol-4-yl
)propionic acid gave
2S-amino-3-(3H-imidazol-4-yl)-N-›1-(5,7-difluoro-1,2,3,4-tetrahydronaphtha
len-2-yl)-5-thioxo-4,5-dihydro-1H-›1,2,4!triazol-4-yl!propionamide
hydrochloride, m.p. 221.degree.-224.degree. C.;
substituting
(S)-5-methylaminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)
-1,3-dihydroimidazole-2-thione and
(S)-3-(tert-butoxycarbonyl)-2-(tert-butoxycarbonylamino)propionic acid
gave 3S-amino-N-›3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2S-yl)-2-thi
oxo-2,3-dihydro-1H-imidazol-4-ylmethyl!-N-methylsuccinamic acid
hydrochloride; and
substituting
4-amino-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro›1,2
,4!triazole-3-thione and
(S)-3-(tert-butoxycarbonyl)-3-(tert-butoxycarbonylamino)propionic acid
gave 2S-amino-N-›1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-thio
xo-4,5-dihydro-1H-›1,2,4!triazol-4-yl!succinamic acid hydrochloride, m.p.
193.degree.-196.degree. C.
EXAMPLE 52
2R-Amino-3-›1-(4,6-difluoroindan-1-yl)-1-H-imidazol-2-yldisulfanyl!propioni
c Acid Hydrochloride
The following is the preparation of a compound of Formula III in which n is
0, t is 2, R.sup.1 is fluoro at the 5- and 7-position and R.sup.27 is a
group of Formula (g) wherein R.sup.4 and R.sup.5 are each hydro and
R.sup.28 is 2-amino-2-carboxyethyl.
A solution of (R,R')-3,3'-disulfanylbis›tert-butyl
2-(tert-butoxycarbonyl)aminopropionate (1.06 g, 2.0 mmol) in 5 mL of
ethylenedichloride was cooled to -23.degree. C. under argon. Bromine (51.3
.mu.L, 1.0 mmol) was added dropwise and the mixture was stirred for
approximately 20 minutes and then diluted with an additional 2 mL of
ethylenedichloride. A suspension of potassium phthalimide (370 mg, 2.0
mmol) in 5 mL of ethylenedichloride was cooled to approximately
-23.degree. C. and the disulfide mixture was added. The mixture was
stirred for 1 hour at -23.degree. C. and then warmed to room temperature
over 45 minutes. The mixture was filtered and concentrated in vacuo. The
residue was dissolved in benzene. Purification by chromatography gave
(R)-N-›2-(tert-butoxycarbonylamino)-2-(tert-butoxycarbonyl)ethylsulfanyl!p
hthalimide (684 mg) as an oil.
A mixture of
(R)-N-›2-(tert-butoxycarbonylamino)-2-(tert-butoxycarbonyl)ethylsulfanyl!p
hthalimide (660 mg, 1.61 mmol) and
1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione (400 mg, 1.59
mmol), prepared as in Example 9, in 8 mL of ethyl acetate was heated at
reflux under argon for 1 hour. The mixture was allowed to cool to room
temperature giving a crystalline precipitate and then the solvents were
removed by evaporation under reduced pressure. The remaining semisolid was
triturated with benzene and the benzene mixture was filtered. The benzene
solution was concentrated by evaporation. Purification of the residue by
chromatography gave tert-butyl
2R-(tert-butoxycarbonyl)amino-3-›1-(4,6-difluoroindan-1-yl)-1H-imidazol-2-
yldisulfanyl!propionate (672 mg) .
A mixture of tert-butyl
2R-(tert-butoxycarbonyl)amino-3-›1-(4,6-difluoroindan-1-yl)-1H-imidazol-2-
yldisulfanyl!propionate (672 mg) in 15 mL of trifluoroacetic acid and 15 mL
of methylenechloride was stirred at room temperature under a nitrogen
atmosphere for 2 hours. The solvent was removed by evaporation and the
residue was co-evaporated with ethyl acetate (2.times.50 mL).
Treatment with ethereal hydrogen chloride gave
2R-amino-3-›5-aminomethyl-1-(4,6-difluoroindan-1-yl)-1H-imidazol-2-yldisul
fanyl!propionic acid hydrochloride (768 mg, 1.74 mmol) as a solid, m.p.
147.degree.-154.degree. C.
Proceeding as in Example 52, but substituting a different starting material
for (R,R')-3,3'-disulfanylbis›tert-butyl
2-(tert-butoxycarbonyl)aminopropionate and/or
1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione gave the
following compounds of Formula III:
substituting (R,R')-3,3'-disulfanylbis›methyl
2-(tert-butoxycarbonyl)aminopropionate! gave methyl
2R-amino-3-›5-aminomethyl-1-(4,6-difluoroindan-1-yl)imidazol-2-yl-disulfan
yl!propionate hydrochloride, m.p. 155.degree.-157.degree. C.;
substituting 3,3'-disulfanylbis›2-(tert-butoxycarbonyl)aminoethyl! gave
2-(2-aminoethyldisulfanyl)-1-(4,6-difluoroindan-1-yl)imidazole
hydrochloride, m.p. 175.degree.-177.degree. C.;
substituting (R,R')-3,3'-disulfanylbis›methyl
2-(trifluoroacetyl)aminopropionate! gave methyl
2-(trifluoroacetyl)amino-3-›1-(4,6-difluoroindan-1-yl)imidazol-2-yl-disulf
anyl!aminopropionate as an oil;
substituting (R,R')-3,3'-disulfanylbis›tert-butyl
2-(tert-butoxycarbonyl)aminopropionate gave
2R-amino-3-›1-(4,6-difluoroindan-2-yl)imidazol-2-yldisulfanyl!propionic
acid hydrochloride, m.p. 145.degree.-150.degree. C.;
substituting 1-(4,5-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione gave
2R-amino-3-›1-(4,5-difluoroindan-2-yl)-1H-imidazol-2-yldisulfanyl!propioni
c acid hydrochloride, m.p. 140.degree. C.;
substituting
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione gave
2R-amino-3-›1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazol
-2-yldisulfanyl!propionic acid hydrochloride, m.p. 130.degree. C.;
substituting
1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione gave
2R-amino-3-›1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazol
-2-yldisulfanyl!propionic acid hydrochloride, m.p. 141.degree. C.;
substituting
1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-
thione gave
2R-amino-3-›1-(6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazol
-2-yldisulfanyl!propionic acid hydrochloride, m.p. 130.degree. C.;
substituting
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-1,3-dihydro-im
idazole-5-carboxylic acid gave
2R-amino-3-›5-carboxy-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)im
idazol-2-yl-disulfanyl!propionic acid hydrochloride, m.p.
129.degree.-138.degree. C.;
substituting 1-(4,5-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione and
(S,S')-4,4'-disulfanylbis›tert-butyl 2-(tert-butoxycarbonyl)aminobutyrate!
gave
2S-amino-4-›1-(4,5-difluoroindan-2-yl)imidazol-2-yl-disulfanyl!butyric aci
d hydrochloride, m.p. 146.degree. C.;
substituting 1-(4,5-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione and
3,3'-disulfanylbis›2-(tert-butoxycarbonyl)aminoethyl! gave
2-(2-aminoethyldisulfanyl)-1-(4,5-difluoroindan-2-yl)imidazole
hydrochloride, m.p. 59.degree. C.;
substituting 1-(4,5-difluoroindan-2-yl)-1,3-dihydroimidazole-2-thione and
(S,S')-3,3'-disulfanylbis›tert-butyl
2-(tert-butoxycarbonyl)amino-3-methylbutyrate! gave
2S-amino-3-›1-(4,5-difluoroindan-2-yl)-1-H-imidazol-2-yldisulfanyl!-3-meth
ylbutyric acid hydrochloride, m.p. 143.degree.-149.degree. C.;
substituting
1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5(1H)-tetrazol-5-yl-1,3
-dihydroimidazole-2-thione and
3,3'-disulfanylbis›2-(tert-butoxycarbonyl)aminoethyl! gave
2-(2-aminoethyldisulfanyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-
yl)-5(1H)-tetrazol-5-yl-1,3-dihydroimidazole hydrochloride, m.p.
165.degree. C. dec; and
substituting
(S)-5-(tert-butoxycarbonyl)aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydron
aphthalen-2-yl)-1,3-dihydroimidazole-2-thione and
(R,R')-3,3'-disulfanylbis›tert-butyl
2-(tert-butoxycarbonyl)aminopropionate gave
2R-amino-3-›5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-y
l)-1H-imidazol-2-yldisulfanyl!propionic acid hydrochloride, m.p.
179.degree.-180.degree. C.
EXAMPLE 53
IN VITRO, DOPAMINE .beta.-HYDROXYLASE INHIBITION
The following describes an in vitro assay to identify compounds that
inhibit dopamine .beta.-hydroylase (DBH). The assay relies upon the
DBH-catalyzed conversion of tyramine to octopamine and the inhibition of
DBH activity by test compounds.
A mixture comprising bovine adrenal DBH (13.8 mUnits/mL), Cu.sup.2+ (2 mM),
ascorbic acid (10 mM), catalase (200 .mu.g/mL), and test compound in 0.65
mL of 50 mM sodium acetate buffer (pH 4.5) was incubated at 37.degree. C.
for 10 minutes. Tyramine was added and the reaction mixture was incubated
at 37.degree. C. for 10 minutes. The reaction was quenched with 0.1 mL of
concentrated ammonium hydroxide. The octopamine product was oxidized to
p-hydroxybenzaldehyde by adding 0.2 mL of 2% sodium metaperiodate and
incubating for an additional 4 minutes. Excess sodium metaperiodate was
reduced with 0.2 mL of 10% sodium bisulfite and the p-hydroxybenzaldehyde
concentration was measured by spectrophotometry at a wave length of 330
nanometers.
Alternatively, a mixture comprising bovine adrenal DBH (0.02 mUnits/mL),
0.125M sodium acetate, 10 mM fumarate, 0.5 .mu.M CuSO.sub.4, 100 .mu.g/mL
catalase and 10 mM tyramine Cu.sup.2+ (2 mM) was incubated at 30.degree.
C. for 5 minutes and then dimethyl-1,4-phenylenediamine (DMPD) was added
to initiate the reaction. The absorbance was monitored continously by
spectrophotometry at a wave length of 515 nanometers.
The test compounds were assayed over a wide range of concentrations and the
concentration of test compound necessary to produce 50% inhibition of DBH
activity was interpolated.
Proceeding as in Example 53 the compounds of the invention were tested and
found to possess DBH inhibitory activity.
EXAMPLE 54
IN VIVO DOPAMINE .beta.-HYDROXYLASE INHIBITION
The following describes an in vivo assay to identify compounds that inhibit
dopamine .beta.-hydroylase (DBH). The assay relies upon dopamine and
norepinephrine tissue concentrations and the affect of the test compounds
thereon.
Male, normotensive or spontaneously hypertensive rats were dosed with
vehicle (1 to 10 mL/kg) or test confound (0.3 to 100 mg/kg) by oral or
intravenous administration. Some rats were dosed 1 to 2 times daily for up
to 24 days. At 2 to 12 hours post final dose, the rats were anesthetized
with halothane and decapitated. Selected tissues (e.g., cerebral cortical,
medullary, mesenteric arterial and left ventricular) were rapidly
harvested, weighed and placed in 0.4 mL of cold perchloric acid. Tissue
concentrations of dopamine and norepinephrine were measured by HPLC and
electrochemical detection methods.
The test compounds were assayed over a wide range of doses and their
effects compared to those of controls. DBH inhibition was defined as a
statistically significant (p.ltoreq.0.05) decrease in norepinephrine
concentration, a concomitant increase in dopamine concentration and an
increase in the dopamine to norepinephrine ratio.
Proceeding as in Example 54 the compounds of the invention were tested and
found to possess DBH inhibitory activity.
EXAMPLE 55
BLOOD PRESSURE LOWERING EFFECTS
The following describes an assay to identify compounds that lower blood
pressure.
Male, spontaneously hypertensive rats were anesthetized and a femoral or
carotid artery was cannulated for continuous blood pressure monitoring.
The rats were allowed 30 to 60 minutes to recover from the anesthesia and
then basal blood pressure levels were obtained. The rats were dosed with
vehicle (10 mL/kg) or test compound (0.3 to 30 mg/kg) by oral or
intravenous administration and followed for 4 to 6 hours.
The test compounds were assayed over a wide range of doses and blood
pressure lowering activity was defined as a statistically significant
(p.ltoreq.0.05) lowering of blood pressure as compared to the vehicle
treated rats.
Proceeding is in Example 55 the compounds of the invention were tested and
found to possess blood pressure lowering activity.
EXAMPLE 56
The following are representative pharmaceutical formulations containing a
compound of Formula I.
ORAL FORMULATION
A representative solution for oral administration contains:
______________________________________
Compound of Formula I 70-700 mg
Citric Acid Monohydrate
105 mg
Sodium Hydroxide 18 mg
Flavoring
Water q.s. to 100 mL
______________________________________
INTRAVENOUS FORMULATION
A representative solution for intravenous administration contains:
______________________________________
Compound of Formula I
7-70 mg
Dextrose Monohydrate
q.s to make isotonic
Citric Acid Monohydrate
1.05 mg
Sodium Hydroxide 0.18 mg
Water for Injection q.s. to 1.0 mL
______________________________________
TABLET FORMULATION
A representative tablet form of a compound of Formula I may contain:
______________________________________
Compound of Formula I
25%
Microcrystalline cellulose
54%
Stearic Acid 20%
Colloidal Silica 1%
______________________________________
Proceeding as in Example 56 representative pharmaceutical formulations
containing a compound of Formula II or III can be prepared.
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